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Review

Beyond PD-1/PD-L1 Inhibition: What the Future Holds for Breast Cancer Immunotherapy

by
Sebastian Chrétien
,
Ioannis Zerdes
,
Jonas Bergh
,
Alexios Matikas
and
Theodoros Foukakis
*
Department of Oncology - Pathology, Karolinska Institutet, 171 76 Stockholm, Sweden
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(5), 628; https://doi.org/10.3390/cancers11050628
Submission received: 8 April 2019 / Revised: 1 May 2019 / Accepted: 2 May 2019 / Published: 5 May 2019
(This article belongs to the Special Issue Signaling Pathways and Immune Checkpoint Regulation in Cancer)
Browse Figure
Versions Notes

Abstract

:
Cancer immunotherapy has altered the management of human malignancies, improving outcomes in an expanding list of diseases. Breast cancer - presumably due to its perceived low immunogenicity - is a late addition to this list. Furthermore, most of the focus has been on the triple negative subtype because of its higher tumor mutational load and lymphocyte-enriched stroma, although emerging data show promise on the other breast cancer subtypes as well. To this point the clinical use of immunotherapy is limited to the inhibition of two immune checkpoints, Programmed Cell Death Protein 1 (PD-1) and Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4). Consistent with the complexity of the regulation of the tumor – host interactions and their lack of reliance on a single regulatory pathway, combinatory approaches have shown improved efficacy albeit at the cost of increased toxicity. Beyond those two checkpoints though, a large number of co-stimulatory or co-inhibitory molecules play major roles on tumor evasion from immunosurveillance. These molecules likely represent future targets of immunotherapy provided that the promise shown in early data is translated into improved patient survival in randomized trials. The biological role, prognostic and predictive implications regarding breast cancer and early clinical efforts on exploiting these immune-related therapeutic targets are herein reviewed.

1. Introduction

The recognition of the importance of the tumor – host interactions in the prognosis of cancer patients significantly predates the current era of cancer immunotherapy. The gradual deciphering of these complex interactions is summarized in the conceptual framework laid out by Hanahan and Weinberg [1], where immunoediting is suggested as a driving force guiding tumor progression. Exploiting these advances only in part, cancer treatment by the inhibition of negative regulators has revolutionized the management of multiple human malignancies, culminating with the award of the 2018 Nobel Prize in Physiology or Medicine – the first ever bestowed upon research related to an anticancer therapy [2].
Beyond its utility as a treatment target, immune response to cancer has also been a subject of research concerning its role as both a prognostic and predictive biomarker. As an example, higher tumor-infiltrating lymphocyte (TIL) counts and expression of immune function genes have been shown to predict better outcomes in most breast cancer (BC) subtypes and increased rates of pathologic complete remission (pCR) following the administration of neoadjuvant chemotherapy (NACT) for early BC (EBC) [3,4]. In metastatic BC (MBC), TIL enumeration has not proven to be as successful [5], since TIL counts have been shown to be lower in metastatic sites compared to the primary tumor [6]. On the other hand, Programmed Cell Death Protein 1 (PD-1) and its ligand PD-L1, as well as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), have been extensively evaluated as putative markers of response to immunotherapy with PD-1/PD-L1 and CTLA-4 blockade, respectively [7,8]. Although data stemming from randomized clinical trials in various human cancers are conflicting, in MBC only one phase 3 trial has been reported demonstrating increased benefit from the combination of atezolizumab and nab-paclitaxel compared to nab-paclitaxel alone in patients whose tumors expressed PD-L1 [9]. PD-1/PD-L1 and CTLA-4 checkpoint inhibitors are already the focus of advanced clinical trials (reviewed by Adams et al. [10]).
Despite the aforementioned exciting developments, it is clear that only a fraction of the potential immunologic therapeutic targets has been comprehensively characterized. Unfortunately, research on immunotherapy for BC has lagged behind due to its perceived lower immunogenicity [11]. Nevertheless, a growing body of literature focusing on a large number of co-stimulatory and inhibitory molecules suggests that the field of cancer immunotherapy in general, and BC in particular, is only in its early stages of development. Herein, we summarize available data on novel immunotherapy targets with a focus on BC (Figure 1).

2. Markers Predominantly Expressed on T-lymphocytes

2.1. LAG-3

Lymphocyte activation gene-3 (LAG-3) is a cluster of differentiation 4 (CD4) related negative regulator of immune response considered as a marker of T-cell exhaustion. It is expressed on both effector and regulatory T-cells, Natural Killer (NK)-cells, B-cells and dendritic cells (DC) [12,13,14,15,16]. Identified LAG-3 ligands are MHC (Major Histocompatibility Complex) class II molecules expressed on antigen presenting cells (APC), LSECTin and Galectin-3 [17,18]. LAG-3 is thought to inhibit the activity and expansion of effector T-cells and enhances the suppressive activity of T-regulatory lymphocytes (Tregs) [19,20,21,22].
Published data on the role of LAG-3 in BC indicate that it is overexpressed in the tumor compared to the adjacent healthy breast tissue [23,24,25], while its overexpression has been associated with improved patient outcomes [26] (Table 1). Following promising pre-clinical results, LAG-3 inhibitors are currently being tested in early phase clinical trials including BC, as monotherapy or in combination with chemotherapy or anti-PD-1 therapy (Table 2). One phase I/II clinical trial testing IMP321 (Eftilagimod), a recombinant soluble LAG-3 Ig (Immunoglobulin) fusion protein, in combination with weekly paclitaxel as a first line treatment in 30 patients with MBC showed promising results, with a response rate of 50% [27].

2.2. TIM-3

T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is a negative regulator of adaptive and innate immune responses. It is expressed on CD8+ and CD4+ T helper 1 cells (Th1 cells), Tregs, NK cells, DC, monocytes and macrophages [89,90,91,92]. Known ligands to TIM-3 are Galectin-9, Ceacam1, HMGB1 (High Mobility Group Box 1) and phosphatidylserine, all expressed by a variety of cells including tumor cells [93,94,95,96]. TIM-3 induces an immunosuppressive environment by suppressing effector Th1 response [93], regulating CD8+ T cell exhaustion [97] and enhancing the regulating function of Tregs [90,98]. It also inhibits the stimulation of the innate immune response by competing with tumor-derived nucleic acids to bind HMGB1 and promoting the expansion of myeloid-derived suppressor cells (MDSC) [95,99].
TIM-3 seems to be upregulated both in BC samples compared to normal adjacent tissue and circulating lymphocytes, possibly through hypomethylation of its promoter [23,29] (Table 1). However, expression on immune cells has been reported to vary widely [29,100]. Burugu et al. evaluated TIM-3 IHC expression in 3992 BC samples of all subtypes and found that the TIM-3 intraepithelial TIL infiltration is associated with a better outcome [32]. TIM-3 polymorphisms might also play a role in the susceptibility to, and prognosis of BC [101,102,103].
Drugs targeting TIM-3 are currently being tested in early phase clinical trials including BC, alone or in combination with anti-PD1/PD-L1 check point inhibitors, with no published results yet (Table 2).

2.3. VISTA

V-domain Ig suppressor of T cell activation (VISTA) is a negative regulator of the T-cell immune activity functioning both as a ligand and receptor [104]. It has been shown to be expressed by CD4+ and CD8+ T-cells, Tregs, DC, NK-cells, monocytes, macrophages and granulocytes [105,106], as well as tumor cells [107,108,109]. VISTA exerts its immunosuppressive function by decreasing the T-cell production of effector cytokines, diminishing T-cell proliferation and increasing conversion to Tregs [106]. To our knowledge, VISTA’s expression and prognostic impact in BC has never been assessed, although a phase 1 clinical trial which enrolls TNBC patients and tests an oral inhibitor of PD-L1, PD-L2 and VISTA is currently ongoing (Table 2).

2.4. TIGIT

T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is a co-inhibitory molecule expressed on effector, memory and regulatory T-cells, follicular helper (Tfh) and NK-cells [110,111]. It competes with CD223 to bind its two identified ligands, CD155 and CD112, expressed on APC, fibroblasts, endothelial, epithelial cells and also on a variety of cancer cells, including BC [112]. TIGIT has different ways of exerting its immunosuppressive action: Direct inhibition of NK-cell function [113], direct inhibition of T-cell activation, proliferation and cytotoxicity by attenuating TCR-driven (T-cell receptor) activation signals [114] and indirect inhibition of T-cells by promoting the maturation of immunoregulatory DCs [111]. It also promotes the Tregs function by being a direct target to FoxP3 (Forkhead box P3) and inducing an enhanced suppressive function [115,116].
TIGIT expression in BC has only been assessed at the transcriptomic level, with most studies showing overexpression [23,31,33,117] (Table 1). In one study, overexpression was correlated with improved patient survival in TNBC [33], leading to the development of antibodies targeting TIGIT in combination with PD-1 blockade (Table 2).

2.5. GITR

Glucocorticoid-induced TNFR-related protein (GITR) is a co-stimulatory member of the tumor necrosis factor (TNF) receptor superfamily expressed constitutively on all T-cells [118,119]. It is also expressed on NK-cells, eosinophils, basophils, macrophages and B-cells [120]. Its activating ligand is the GITR ligand (GITRL), expressed on APC and endothelial cells [121,122]. Upon binding, GITR exerts an immunostimulatory activity by directly enhancing T-cell proliferation and effector functions [123,124]. It also indirectly enhances the effector T-cell function by decreasing the intratumoral Treg numbers and suppressive function [125,126]. By avoiding activation-induced cell death, it also promotes an increase in memory T-cells [127].
Cari et al. assessed GITR mRNA expression in 3169 BC patients of all subtypes and found an overexpression in 42% of the cases [31]. Other studies demonstrated that expression is increased in both infiltrating [34] and circulating Tregs of BC patients [35,37]. Interestingly, GITR seems to also be overexpressed in CD4+ T-cells in BC-infiltrated lymph nodes [36] (Table 1).
BMS-986156, a GITR agonistic monoclonal antibody, in combination with nivolumab has demonstrated an acceptable safety profile and promising antitumor activity in advanced solid tumors [82]. Other agonist molecules targeting GITR are currently being tested in early phase clinical trials (Table 2).

2.6. B7-H3

B7 homolog 3 (B7-H3) is a member of the B7 family of immunomodulatory ligands. It is not spontaneously expressed in peripheral blood mononuclear cells but can be induced upon stimulation in APC, T-cells and NK-cells [128]. It is widely expressed in healthy solid organs and several malignancies, including BC [129]. Interestingly, it is also expressed by tumor-associated endothelial cells [45]. Although B7-H3 was initially seen as a co-stimulatory molecule, which increases CD4+ and CD8+ proliferation and enhances T cell cytotoxicity [129,130], the majority of recent studies highlight its co-inhibitory role. Indeed, it appears to downregulate T-cell proliferation and cytokine production [131], Th1 and Th2-mediated immune reactions [132] and inhibit NK cells activity [133]. Moreover, B7-H3 seems to influence cancer progression beyond its immunoregulatory role, by promoting migration, invasion and angiogenesis [134,135].
B7-H3 expression in BC has been extensively studied and demonstrated to confer worse prognosis [41,42] (Table 1). As a result, two antagonist drugs – a monoclonal antibody (enoblituzumab) and a dual-affinity re-targeting (DART®) protein (MGD009) – are currently under evaluation in early phase clinical trials including BC (Table 2).

2.7. ICOS

Inducible T cell co-stimulator (ICOS) is a specific T-cell molecule of the B7-binding CD28 family, expressed on activated T-cells after TCR engagement and enhanced by CD28 co-stimulation [136,137]. Its only ligand is ICOS-L, mainly expressed on APC [138,139,140] but also on endothelial and lung epithelial cells [141,142]. Although typically seen as an immune co-stimulatory pathway, notably through promoting cell proliferation/differentiation, enhancing Th1/Th2 function and facilitating T-dependent B-cell activation [136,137,143], ICOS/ICOS-L interaction might also have an immunosuppressive role through the accumulation of Tregs and secretion of IL-10 [46,144].
In a study by Faget et al., BC patients overexpressing ICOS had a significantly worse survival in the univariate but not multivariate analysis [46], while certain ICOS gene polymorphisms have also been associated with increased BC susceptibility in Chinese populations [145,146] (Table 1). Ongoing trials of agents targeting ICOS are shown in Table 2.

2.8. 4-1BB (CD137)

4-1BB (CD137) is a member of the TNF receptor superfamily, widely expressed on adaptive and innate immune cells like effector, helper and regulatory T-cells [147,148], B-cells [149], NK-cells [150,151], DCs [152], neutrophils, eosinophils, mast cells, monocytes and macrophages [153]. It is also expressed by a variety of other non-immunological cells, including endothelial and malignant hematological cells [154]. It exerts a co-stimulatory action upon ligation with its ligand 4-1BBL, resulting in enhanced T-cell and NK-cell proliferations, production of pro-inflammatory cytokines and cytotoxicity [150,155,156] and the inhibition of activation-induced cell-death in T-cells [157].
Two studies using gene-expression datasets demonstrated that 4-1BB is overexpressed in BC and is associated with better prognosis [31,47] (Table 1).
Monoclonal agonist antibodies are currently being tested in early phase clinical trials including BC (Table 2). Two early-phase studies (NCT00351325 and NCT00309023) raised concerns due to two hepatotoxicity-related deaths, though not replicated in a follow-up phase 1 study [158].

2.9. CD27 and CD70

CD27 and its only ligand CD70, are members of the TNF receptor and ligand superfamily that interact exclusively with each other. CD27 expression on T-cells is tightly regulated, with upregulation upon activation after the TCR stimulation followed by downregulation once the effector T-cell differentiation is acquired [159]. CD27 is also expressed on B-cells (germinal center and memory B-cells) and NK-cells [160,161,162]. CD70 expression on immune cells is also tightly regulated and is present on activated T-cells, stimulated B-cells, mature DC and NK-cells [163,164,165,166]. Interestingly, CD70 has also been found to be expressed in various hematological, sarcoma and carcinoma cells including BC [167]. The CD27-CD70 pathway exerts its co-stimulatory activity in great part through CD27 interaction with TNF receptor associated factors (TRAF), resulting in the activation of transcription factors of MAPK (Mitogen-activated Protein Kinase) and NFκB (Nuclear Factor kappa-light-chain-enhancer of activated B-cells) family. This leads to the expansion and survival of activated T cells [168,169,170,171,172,173]; differentiation to memory and effector T-cells [173,174,175]; activation of NK-cells [176,177]; and differentiation plus activation of B-cells [178,179,180].
CD70 protein expression in BC was assessed in two studies with contrasting results [49,50] (Table 1). Of interest, Liu et al. demonstrated that a high CD70 expression was correlated with worse lung metastasis-free survival, but not with other metastatic sites following relapse of EBC. In addition, gene expression studies showed that CD70 was overexpressed in basal-like compared to Luminal A cancers and that overexpression after NACT was associated with a better outcome [51,181].
Two antibodies, ARGX-110 targeting CD70 and CDX-1127 (Varlilumab) targeting CD27 are currently in early phase clinical trials. In addition, a trial is testing the safety and activity of administering peripheral blood lymphocytes transduced with a CD70-binding Chimeric Antigen Receptor (CAR) to patients with CD70-expressing cancers (Table 2).

2.10. OX40 and OX40L

OX40 (CD134) and OX40L are members of the TNF superfamily. OX40 is constitutively expressed on Tregs and transiently induced on activated CD4+ and CD8+ T-cells following TCR stimulation [182,183,184]. It has also been reported to be expressed by neutrophils, NK-cells and NKT-cells [185,186,187]. Its ligand, OX40L, is expressed on professional APC, NK-cells, Langerhans cells, vascular endothelial cells, monocytes, neutrophils and mast cells. Like OX40, it is upregulated upon activation [188,189,190,191,192,193,194,195]. OX40-OX40L interaction, like other TNF members, exerts a co-stimulatory effect through interacting with TRAF, which impacts CD4+ and CD8+ T cells by enhancing their proliferation and survival, generating memory cells, enhancing their effector function and promoting differentiation into Th1, Th2 and Th17 cells through various cytokines production [196,197,198,199,200,201,202,203].
Several studies have assessed OX40 expression in BC, showing an expression varying from 15.5% to 85% of cases (Table 1). Interestingly, Xie et al. reported expression on cancer cells while all the other studies reported expression on TILs [52]. Consequently, a number of agonistic monoclonal antibodies targeting OX40 and a mRNA encoding OX40L (injected intra-tumorally) are currently being tested in early phase clinical trials including BC, alone or in combination with other immunotherapies. (Table 2)

2.11. BTLA

BTLA (B and T Lymphocyte Attenuator) is an inhibitory Ig-domain-containing glycoprotein receptor of the CD28 superfamily expressed on activated T-cells, B-cells, Tfh cells, macrophages, DC, NKT-cells and NK-cells [204,205,206,207,208]. Its only proven ligand is HVEM (Herpes Virus Enter Mediator), a member of the TNF receptor family, expressed on CD4+ and CD8+ T-cells (strongly on resting T cells, downregulated upon activation), naïve and memory but not activated B-cells, monocytes, DC, solid organs, tumor-associated endothelial cells or on various cancer cells including BC [209,210,211,212]. BTLA has also been described as a potential receptor for B7-H4 in BC [213]. BTLA exerts its T-cell inhibitory action upon binding HVEM, leading to a decreased T-cell proliferation and cytokine production with a predominant effect on CD4+ cells [214,215,216,217,218,219]. Data concerning its action on B-cell function is scarce but it appears to negatively regulate B-cell activation [220]. Interestingly, BTLA and PD-1 seem to be co-expressed on CD8+ T-cells.
Data concerning BTLA expression in BC is scarce (Table 1). Although it seems to be overexpressed at the transcriptomic level, especially in TNBC where it was also associated with improved survival [57], protein expression appeared to be limited in another study [58]. To our knowledge, no clinical trials for therapeutic targeting of BTLA are currently ongoing.

2.12. TLR9

Toll-like receptors (TLRs) are type I transmembrane glycoproteins of the pattern recognition receptors (PRR). They play a key role in immunity by allowing immune cells to recognize non-self or altered-self molecular patterns, activating the innate immune response and coordinating the innate and adaptive immune responses. The most studied member in BC is the intracellular receptor TLR9.
TLR9 is a DNA receptor that migrates from the endoplasmic reticulum to the endosomal/lysosomal compartment when DNA enters the cell [221,222]. When activated by DNA recognition, TLR9 initiates a signaling cascade [222,223], leading to the activation of various transcription factors like NF-κB and AP-1 (Activator protein 1) [224], thus promoting the transcription of genes that are important for inflammatory and immune responses [225,226]. In addition, it promotes adaptive immunity by enhancing DC maturation and producing a favorable cytokine/chemokine milieu that results in the activation of Th1 and CD8 cytotoxic T lymphocytes as well as by promoting B-cell proliferation [227,228].
TLR9 expression and its prognostic role in BC has been reported by several studies with conflicting results [60,64] (Table 1). Nevertheless, it appears that TLR9 is expressed at higher levels in estrogen receptor (ER) negative and high-grade tumors. Regarding the prognostic significance of TLR9 expression, three studies associated high expression with a better outcome [60,61,64], while two other studies reported worse survival [63,66]. Of interest, Karki et al. demonstrated that BC patients have decreased serum levels of TLR9 compared to patients with benign lesions and healthy controls, proposing it as a potential diagnostic biomarker [229]. Moreover, several but not all studies have shown an association between TLR9 gene polymorphisms and BC susceptibility [230,231,232,233].
Therapeutic targeting of TLR9 has proven to be efficient in pre-clinical models of various cancers including BC and many drugs are currently being tested in several cancer types, some of them even reaching phase III (NCT03445533) (Table 2).

2.13. The Adenosine Pathway in Breast Cancer

The adenosine pathway is an important peripheral control mechanism for regulating the immune response in order to prevent over-activation and tissue damage. As with other immunoregulatory pathways, cancer cells are capable of hijacking it in order to promote tumor escape. Important components of this pathway are the adenosine receptor A2a (A2aR), through which the extracellular adenosine can activate its intracellular signaling pathway and the ectonucleotidases CD39 and CD73, which participate in extracellular adenosine production by dephosphorylating ATP.
A2aR is a G-protein-coupled receptor expressed on T and NKT-cells, B-cells, monocytes, macrophages, DC, NK-cells, mast cells, eosinophils and platelets [234]. CD73 is a cell-surface enzyme that can also be found as an enzymatically active soluble form. It is widely expressed on immune cells including B-cells, CD8+ and CD4+ T-cells, Tregs, neutrophils, MDSC, monocytes, macrophages, DC and NK-cells [235]. It is also expressed on a wide range of epithelial cells, endothelial cells and cancer cells including BC [235,236,237]. CD39, another cell-surface enzyme which produces adenosine, is also expressed on a variety of immune cells [238,239,240]. It is also expressed on platelets, endothelial cells and cancer cells including lung, melanoma, pancreatic and lymphoma cells [241,242,243]. Like CD73, a soluble catalytically active form of CD39 exists [244]
The adenosine pathway exerts an immunosuppressive action by inhibiting effector T-cell activation [245], proliferation, cytokine production and cytotoxicity as well as promoting their immunosuppressive cytokine production [246,247]. In addition, it promotes Tregs formation [246], inhibits NK-cell antitumor activity [248], NKT-cell production of cytokines [249], macrophage proliferation [250] and DC maturation [251]. It has also been shown to increase the expression of other immune checkpoints [252].
CD73 expression on BC cells ranges from 9 to 84% of the cases and is generally associated with worse outcome, although one study reported contrasting results [68] (Table 1). In addition, CD39 is overexpressed both in TILs and circulating T cells of BC patients when compared to healthy controls, but its prognostic value has not been studied.
Numerous pre-clinical studies have demonstrated the efficacy of targeting the adenosine pathway in BC models, leading to the development of A2aR oral inhibitors and antibodies targeting CD73, currently in early phase clinical trials (Table 2). CD39 targeting therapies are currently under pre-clinical development but to our knowledge none have yet reached clinical trials.

3. Tumor-Associated Macrophages and Related Markers

Tumor-associated macrophages (TAMs) represent a major and heterogeneous distinct immune cell subpopulation in the tumor microenvironment (TME). In many tumor types, including BC, TAMs play a key role in tumor progression, angiogenesis, immune evasion and metastasis [253]. They also interact with other cell types through the secretion of various cytokines which in turn can modify the balance between tumor, stromal, endothelial and immune cells. According to the markers expressed on their cell surface as well as the factors they secrete, TAMs can be divided into two subtypes: a) the classically activated M1-like macrophages which have pro-inflammatory, anti-tumoral properties mainly through the secretion of TNF-a (Tissue Necrosis Factor alpha), IL-1, IL-2, IL-6, IL-12; and b) the selectively activated M2-like macrophages with anti-inflammatory, pro-tumoral phenotype mainly through TGF-β (Transforming growth factor beta), IL-4, IL-10 and IL-13 [254]. In terms of prognosis, TAMs were associated with worse overall survival in many solid tumors according to a large meta-analysis [255]. In BC in particular, a meta-analysis of sixteen studies revealed that a high TAM density was associated with worse overall survival (Hazard Ratio [HR]=1.50; 95% Confidence Intervals [CI] 1.20-1.88) and disease-free survival (HR=2.22; 95% CI 1.71-2.89) [256]. Overall, therapeutic strategies against TAMs are based on two major approaches: a) targeting TAM recruitment and activation, and b) reprogramming macrophage polarization towards an anti-tumoral phenotype. The first approach includes the elimination of TAM and monocyte accrual to the tumor site through the inhibition of mainly CSF-1/CSF-1R (Colony Stimulating Factor 1/ Colony Stimulating Factor 1 Receptor) and CCL2/CCR2 (C-C Motif Chemokine Ligand 2/ C-C Motif Chemokine Receptor 2) signaling axes. The second approach relies on the fact that TAMs are mostly of the M2-like phenotype and thus, stimulating the properties of the M1-like phenotype could be an effective treatment option to restore anti-tumoral activity. Such potential treatments for the macrophage polarization shift include CD40-agonists and/or TLR7 agonists. Whether the aforementioned therapeutic agents can be combined with other therapies which can target angiogenesis, increase phagocytic activity or enhance anti-tumor immunity is currently under investigation [257,258]. Moreover, recognition and targeting of other pro-tumoral chemokines and cytokines [259] or novel targets could broaden the therapeutic spectrum in cancer immunotherapy.

3.1. CSF-1/CSF-1R

TAM recruitment is highly controlled by the interaction of the glycoprotein CSF-1 with its receptor CSF-1R, a member of type III receptor tyrosine kinase family. Binding of CSF-1 to CSF-1R leads to activation, recruitment and proliferation of TAMs [260]. CSF-1R is normally expressed in various cell types but its expression in BC cells has been correlated to worse prognosis [261,262,263,264] (Table 3). Therapeutic targeting of this axis is under active investigation (Table 4).

3.2. CCR2/CCL2

The recruitment of circulating monocytes from the bone marrow into the TME is also mediated by the expression of the chemokine ligand CCL2. The binding to its receptor CCR2 leads to the differentiation of monocytes into TAMs and to the subsequent promotion of their pro-tumoral activity, tumor cell proliferation, angiogenesis and metastatic dissemination [265,266]. Expression of these chemo-attractants has been linked to worse prognosis in BC patients [267,268,269,270,271] (Table 3). Targeting this axis using CCR2 antagonists and anti-CCL2 antibodies is currently being explored in advanced solid malignancies, including BC (Table 4).

3.3. CD47 and SIRPa

Interaction between the two cell-surface immunoglobulin family members, CD47 and signal regulatory protein alpha (SIRPα), is crucial for the regulation of phagocytosis. CD47 is expressed on cancer cells while SIRPα is expressed on macrophages. Upon interaction, the anti-tumor immunity is diminished as CD47 represents a ‘don’t eat me’ signal, thus impairing phagocytosis [296,297]. Through targeting this checkpoint axis using anti-CD47 antibodies, CD47-Fc and/or SIRPα-Fc fusion proteins, the macrophage phagocytic capacity can be restored (antibody-dependent cellular phagocytosis, ADCP) towards an effective immune response. The first reported efficacy results of the Hu5F9-G4 inhibitor combined with rituximab in non-Hodgkin’s lymphoma are promising [298]. Possible synergistic effects of such treatments with anti-HER2 or anti-PD-L1/PD-1 antibodies are being tested in clinical trials (Table 4).

3.4. TLR7

TLR7 represents an intracellular receptor, member of the toll-like receptors transmembrane glycoprotein family. Its expression can enhance the DC function and can re-programme macrophages towards an anti-tumoral M1 phenotype [299,300]. Therefore, its activation using TLR7 agonists could provide effective anti-tumor responses. Indeed, the use of the topical TLR7-agonist imiquimod in combination with nab-paclitaxel led to the short-term regression of BC cutaneous metastases in early phase trials [301,302] (Table 4).

3.5. CD40

CD40 represents a co-stimulatory protein, member of the TNF receptor family and is an emerging target in cancer immunotherapy. CD40 is mostly expressed by APC and macrophages and binding of its ligand (CD40L) on T-cells results in T-cell activation [303]. Preclinical data of the CD40-agonist efficacy have been reported in BC and other tumor types, demonstrating the promotion of T-cell responses [304,305]. CD40 activation using agonistic monoclonal antibodies can also lead to the enhancement of macrophage tumoricidal and pro-inflammatory properties mainly through MHC-II upregulation [303]. Preliminary results indicate activity and durable immune responses [306] (Table 4).

4. Natural-Killer Cells and Related Markers

4.1. Killer Immunoglobin Receptors (KIR)

NK-cells represent an immune cell subpopulation with an active role in effective antitumor immunity [307]. MHC class I specific Killer Immunoglobin Receptor (KIR) family members are mostly expressed on the surface of NK-cells. Some KIR - upon binding to their ligands HLA-B or HLA-C - can hinder NK cell activation [308], while others are associated with NK stimulatory properties and better prognosis for cancer patients [309,310]. Ongoing clinical trials are underway, testing antibodies against NK-inhibiting KIR family members in combination with other immune checkpoint inhibitors (Table 4).

4.2. CD94/NKG2A

NK group member 2A (NKG2A) represents a novel inhibitory receptor, which forms heterodimers with CD94, both belonging to the C-type lectin-like family and expressed mainly on the surface of NK-cells and also on CD8+ T-cells. Upon binding of the complex to its MHC class I (HLA-E) ligand, the anti-tumoral capacity of NK-cells can be hindered and an immunosuppressive phenotype through T-cell inactivation is established [308,311]. Recently, two preclinical studies in colorectal and head and neck carcinoma demonstrated that blockade of this receptor may be a new appealing immunotherapeutic target [312,313]. Expression of NKG2A has been described in BC patients [273], however no studies on therapeutic targeting are ongoing (Table 3).

4.3. NK-Cell Activating Receptors

NK-cells are activated through various receptors such as the natural cytotoxicity receptor (NCR) family (NCR1 or NKp46, NCR2 or NKp44, NCR3 or NKp30) and NK group member 2D (NKG2D). The latter recognizes several ligands including MHC class I polypeptide-related sequence (MICA/MICB) and UL16-binding proteins (ULBP1-6) and their interaction leads to enhanced cytolysis [314,315]. Expression of NKG2D ligands has been associated with improved survival in BC [274,316,317] (Table 3).

5. IDO

Indoleamine 2,3 dioxygenase-1 (IDO1) is an enzyme mostly found in DC and an appealing target for cancer immunotherapy [318]. It plays an important role in metabolism-mediated immune regulation by catalyzing the conversion of amino acid tryptophan to kynurenine and thus impairing T-cell activation and promoting Treg expansion [319,320]. IDO expression in BC patients has been extensively studied, with varying positivity, from 14 to 100% of the cases [276,279]. Most of the studies describe a predominant expression by tumor cells with limited expression by stromal dendritic-like cells and occasional expression by myoepithelial cells. Although conflicting results have been reported, the majority of the studies show that the IDO expression is correlated to an advanced stage at diagnosis, high grade, ER negativity and worse outcome [277,278]. Recent findings from a phase I trial, indicate the activity and safety of targeting IDO in combination with anti-PD-L1 monoclonal antibody atezolizumab in various advanced solid tumors including BC [321].

6. Myeloid-Derived Suppressor Cells

MDSCs represent a heterogeneous population of immature myeloid cells including progenitor cells, immature DCs, macrophages and granulocytes. In humans, MDSCs are defined by the positive expression of CD33 and CD11b and negative or reduced expression of HLA-DR. MDSCs are further classified as monocytic or granulocytic MDSCs when CD14 or CD15 is expressed, respectively.
MDSCs play a major role in promoting an immunosuppressive microenvironnment through various mechanisms: Production of reactive oxygen and nitrogen species depleting TILs [322,323], impairment of lymphocyte-homing [324], promotion of other immunosuppressive cells such as Tregs and M2-macrophages [325,326], depletion of metabolites involved in the T cell function such as L-arginine and cysteine [327,328] PD-L1 expression [329] and adenosine production by upregulating the expression of ectonucleosidases CD39 and CD73 [330]. In addition to their immunosuppressive effect, MDSCs also promote tumor dissemination and metastasis by affecting epithelial-mesenchymal transition [331], degradation of extra-cellular matrix [332], stem cell formation [333], angiogenesis and formation of premetastatic niches [334,335].
Presence of MDSCs in BC patients has been studied both in peripheral blood and primary tumors. Patients with BC have elevated levels of circulating MDSCs compared to healthy donors or patients with benign lesions and the levels of MDSCs increase with tumor burden (i.e. clinical stage), making it a potential tool for BC diagnosis [336,337]. MDSCs are also present in the BC tumor microenvironment at significantly higher levels than the adjacent healthy breast tissue and one study found that TNBC seems to be more infiltrated than other BC subtypes [338,339,340]. Moreover, MDSCs represent a potential biomarker for predicting both survival and response to NACT, with higher levels of circulating of infiltrating MDSCs being associated with worse survival and pCR rates [340,341,342,343].
As a result, targeting MDSCs is a putative therapeutic tool for BC patients and different strategies have shown promising results in pre-clinical studies [344,345,346,347]. Briefly, current treatment strategies aim to modulate myelopoïesis by forcing differentiation into mature cells or inhibiting maturation from precursor cells, block MDSC accumulation in tumor sites and block MDSC immunosuppressive functions [348]. To our knowledge, only pre-clinical data of MDSC targeting in BC have been published but three early-phase clinical trials are currently ongoing (NCT03145012; NCT02922764; NCT02499328).

7. Implementing Combination Immunotherapy in the Clinic

Blockade of the PD-1/PD-L1 axis through the use of monoclonal antibodies as monotherapies has met with considerable success during the past decade. The central concept of immunotherapy with the inhibition of negative regulators of the immune response is the restoration of activity of exhausted cytotoxic T-lymphocytes. As evidenced by the observation of responses among patients lacking a local immune response (no PD-1/PD-L1 expression at the protein level, absence of TIL), a pre-existing immune response is not an absolute prerequisite needed for the elicitation of responses to treatment. Nevertheless, response rates and response duration following treatment with a monotherapy seem to be lower among those patients [349].
Intriguingly, the combined immune checkpoint blockade confers superior results compared to PD-1 blockade alone in this patient group. Data derived from the phase 3 CheckMate 067 trial indicate that double PD-1 and CTLA-4 blockade with nivolumab and ipilimumab improved both progression-free (HR=0.67; 95% CI were not reported) and overall survival (HR = 0.70) compared with nivolumab alone in patients with metastatic melanoma and PD-L1 expression lower than 1% [350]. Although this analysis is exploratory and the trial was not designed to perform this comparison, it provides support for immunotherapy combinations. The theoretical background seems intuitive. Mechanistically the two checkpoints function on different sites of immune activation: CTLA-4 carries out its function at the sites of priming whereas PD-1 is responsible for maintaining tolerance by dampening the activation of T-lymphocytes in the periphery [351]. It is unclear however whether the combinatory approach is successful thanks to an additive effect of the two inhibitors or if it results from the suppression of escape mechanisms. Similarly, it is conceivable that the inhibition of other negative regulators or agonistic activation of co-stimulatory molecules in combination with each other or with established immunotherapies can lead to further improvements in terms of patient outcomes. It is clear however that a mechanistic understanding of the biology of the candidate therapeutic targets and of the cross-talk that is activated upon inhibition is of paramount importance. Further underscoring the need for a deep understanding of the underlying biologic processes and the rational design of novel agents is the failure of the combination of the once promising IDO1 inhibitor epacadostat to improve outcomes in combination with pembrolizumab versus pembrolizumab alone in patients with metastatic melanoma [352].
While increased efficacy is the main goal, two barriers need to be overcome for successful integration of novel immunotherapies: Toxicity and financial cost. The clinical use of the checkpoint inhibition is associated with a risk for serious, potentially fatal immune-related adverse events (irAEs). Following this paradigm, the ability to inhibit multiple targets simultaneously may be limited by the adverse event profile of such combinations. It is important to note that while it is unclear whether the same molecular mechanisms that drive tumor rejection are to blame for the induction of irAEs, both retrospective [353] and limited prospective data [354] show a correlation between irAEs and better outcomes. This correlation has not been adequately studied if it also concerns combinatorial immunotherapy, which is associated with a higher risk for severe irAEs according to the aforementioned CheckMate 067 trial [350].
On the other hand, the revolution of cancer immunotherapy has brought to the limelight the associated financial costs. Published data indicate that the combination of nivolumab and ipilimumab, despite its efficacy, is not a cost-effective option [355]. How quickly and widely the combination will be adopted in light of the positive results from randomized trials on malignancies that can be readily treated with other options [356,357], remains to be seen. It is reasonable to assume that future combinations with novel agents will not differ in that respect. In addition, the evaluation of novel combinations will likely be plagued by the same problems that have affected PD-1/PD-L1 inhibitors: Inconclusive predictive biomarkers lacking analytical validity and clinical validity/utility, variety of companion diagnostics using different antibodies and cut-offs, trials reporting different results from different antibodies in the same clinical setting and overabundance of available options with no hints on their differential efficacy [7]. It is therefore imperative that future phase 3 trials will be based on robust preclinical and early clinical data.

8. Conclusions

A large number of co-stimulatory or co-inhibitory molecules regulating tumor evasion from immunosurveillance have been studied in BC (Table 5). As reviewed here, there are solid pre-clinical data on the function of these factors and emerging data on their regulation and their role in the clinical setting. These molecules likely represent future targets of immunotherapy provided that the promise shown in early data is translated into improved patient survival in randomized trials.
While it seems counterintuitive that the development of the next generation of immunotherapy agents precedes the optimization of the currently available ones, early recognition of the most promising agents can hasten their implementation in clinical practice. As we previously characterized the emergence of the PD-1/PD-L1 inhibition as the “end of the beginning” of cancer immunotherapy [7], the exciting advances that are described in this review could very well represent the “beginning of the end” of non-selective cytotoxic chemotherapy.

Author Contributions

Conceptualization, I.Z., A.M. and T.F.; Literature review, S.C. and I.Z.; Writing—initial draft preparation, S.C. and I.Z.; Writing—review and editing, J.B., A.M. and T.F. All authors have read and approved the submitted version of the manuscript.

Funding

This research was funded by Swedish Cancer Society (grant number CAN 2018/846).

Acknowledgments

Alexios Matikas was supported by the Stockholm County Council (clinical postdoctorial appointment). Theodoros Foukakis is recipient of the Senior Clinical Investigator Award from the Swedish Cancer Society (grant number CAN 2017/1043). We thank Ioannis Mantas for his help with the illustrative work.

Conflicts of Interest

Sebastian Chrétien, Ioannis Zerdes and Alexios Matikas have no conflicts of interest to disclose. Theodoros Foukakis: Institutional grants from Roche and Pfizer and personal fees from Novartis, Pfizer, Roche and UpToDate; Jonas Bergh receives research fundings from Merck paid to Karolinska Institutet and from Amgen, Bayer, Pfizer, Roche and Sanofi-Aventis paid to Karolinska University Hospital. No personal payments. Payment from UpToDate for a chapter in breast cancer prediction paid to Asklepios Medicine HB.

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Cancers 11 00628 g001 550
Figure 1. Interplay between tumor cells and immune system components in the tumor microenvironment. Abbreviations for represented cells and immune-related markers are explained in the main text.
Figure 1. Interplay between tumor cells and immune system components in the tumor microenvironment. Abbreviations for represented cells and immune-related markers are explained in the main text.
Cancers 11 00628 g001
Table
Table 1. Expression and prognostic/predictive value of immune-related markers predominantly expressed on T-cells.
Table 1. Expression and prognostic/predictive value of immune-related markers predominantly expressed on T-cells.
MarkerBC
Subtype		Number of PatientsMethodPositive/
Overexpressing Cases		Prognostic/Predictive ValueCommentsReference
LAG-3All8RT-PCRLAG-3 expression: 8/8 (100%)NALAG-3 overexpression in BC compared to adjacent healthy tissue[23]
All148 pre-NACT
114 post-NACT		IHCLAG-3 positivity:
Pre-NACT: 33/148 (22.3%)
Post-NACT: 38/114 (33.3%)		LAG-3 expression: pedictive for pCR in UA but not MAPositive case cut-off: expression ≥ 5%[28]
TNBC259 (training set)
104 (validation set)		IHCLAG-3 positivity: 65/363 (18%)LAG-3 positivity: trend to better RFS and OS in UAPositive case cut-off: expression ≥ 5%[25]
All330 (training set)
3992 (validation set)		IHCLAG-3 positivity:
327/2921 (11%)		LAG-3 positivity: better BCSS and RFS in MA but not when considering CD8, PD-1 and PD-L1Positive case cut-off: ≥ 1 TILs per TMA core
2921 evaluable in validation set		[26]
TIM-3All150IHCBC cases:
TIM-3 + tumor cells 147/150 (98%)
TIM-3+CD8+ T cells 135/150 (90%)Healthy controls:
TIM-3+ epithelial cells 13/100 (13%)
TIM-3+CD8+ T-cells 23/100 (23%)		NA [29]
All20FCNANAPeripheral blood: overexpression of TIM-3 in CD4+CXCR5+ICOS+ T cells compared to healthy controls
TILs: overexpression of TIM-3 in CD4+CXCR5+ICOS+ T cells compared to peripheral blood of same patients		[30]
All8RT-PCRTIM-3 expression: 8/8 (100%)NAOverexpression in BC compared to healthy adjacent tissue[23]
All3169Gene expression datasetNo overexpressionNAUse of gene expression dataset Genevestigator v3[31]
All3992
(3148 evaluable)		IHCTIM-3+ iTILs: 332/3148 (11%)
TIM-3+ sTILs: 630/3148		TIM-3+ iTILs: better BCSS
TIM-3+ sTILs: statistically not significant better BCSS		TIM-3 iTILs cut-off: expression ≥ 1 iTIL
TIM-3 sTILs cut-off: expression ≥ 2 sTILs
TIM-3+ iTILs correlated to basal-like subtype		[32]
VISTANANANANANANANA
TIGITAll3169Gene expression datasetTIGIT overexpression in 72%NAUse of gene expression dataset Genevestigator v3[31]
TNBC47Gene expression datasetNATIGIT overexpression: better RFS and OSUse of gene expression dataset from GEO datasets (GDS2250 and GSE3744)[33]
All8RT-PCRTIGIT expression: 8/8 (100%)NANo overexpression of TIGIT in BC compared to adjacent healthy tissue[23]
GITRAll33FCNANAPT Tregs: 80.5% expression of GITR
Circulating Tregs: 28.9% expression of GITR		[34]
All39FCNANAPT CD4+h T cells: higher GITR expression than healthy control CD4+ T cells [35]
All3169Gene expression datasetGITR overexpression in 42%NAUse of gene expression dataset Genevestigator v3[31]
Not specified3FCNANA [36]
Not specified17FCNANAMore T regs expressing GITR in BC patients than healthy donors (n = 10)[37]
B7-H3All221IHCB7-H3 high expression:
Healthy controls: 14/85 (16.48%)
BC: 178/221 (80.55%)		NA [38]
All82RT-PCRB7-H3 overexpression: 32/82 (39%)NA [39]
All117IHCB7-H3 positivity: 106/117 (90.6%)NAPositive case cut-off: expression > 10%[40]
All90IHCB7-H3 high: 83/90 (92%)B7-H3 high: worse RFS but no association with OS [41]
All74IHC B7-H3 IHC positivity:
BC 42/74 (56.8%)
healthy controls 32/74 (43.2%)		B7-H3 positivity: worse OS [42]
All97IHCNANAB7-H3 expression significantly higher in BC (n=97) compared to normal tissue (n = 53), benign, and precursor lesion (n = 182)[43]
All208IHCB7-H3 positivity:
BC: 154/208 (74%)
Healthy controls: 3/7 (43%)		NA [44]
All101IHCB7-H3 positivity:
BC: 88/101 (88%)
Healthy controls: 6/47 (12.8%)		NA [45]
ICOSAll120IHC
FC		NAICOS positivity:
UA: worse PFS and OS
MA: not significant		Positive case cut-off: expression ≥1.7 positive cells
Tumoral Treg ICOS+: 69.9%
BC circulating Treg ICOS+: 16.6%
Healthy circulating Treg ICOS+: 21.3%		[46]
4-1BBAll3169Gene expression dataset4-1BB overexpression in 42%NAUse of gene expression dataset Genevestigator v3[31]
All286Gene expression datasetNA4-1BB expression: better DFMS [47]
Not specified4IHC4-1BB positivity: 2/4 (50%)NAPositive case cut-off: expression > 10%[48]
CD70All204IHCCD70 positivity: 5/204 (2.45%)NA [49]
All139 (110/139 with metastasis)
233 (stage I – III)		IHCCD70 expression: 81/139 (58.3%)CD70 expression: worse lung MFS [50]
All16 (pre and post-NACT)RT-PCRNACD70 overexpression after NACT: better PFS [51]
OX40 and OX40LAll107
9 DICS		IHCPositivity in PT:
OX40 91/107 (85%)
OX40L 89/107 (83.2%)
Positivity in DCIS:
OX40 6/9 (66.7%)
OX40L 7/9 (77.8%)		NAPositive case cut-off: expression on > 10% tumor cells
OX40 associated with advanced stage		[52]
Not specified19IHCOX40 positivity: 10/19 (52.6%)NAPositive case cut-off: expression on > 10% cells [53]
Not specifiedNot specifiedIHC
FC		OX40+CD4+ TILs in 43% of the BC casesNANo OX40 expression on circulation CD4 T cells[54]
Not specified45IHCOX40 positivity: 7/45 (15.55%) OX40 expressed on TILs
OX40 expression also found on positive LN		[55]
Not specified44IHCOX40 positivity: 7/18 (30%) of theCD4+ casesNA [56]
BTLAAll3080Gene-expression datasetBTLA overexpressed in TNBC compared to non-TNBCBTLA overexpression in TNBC: better OS and DFSUse of gene expression profiles of breast invasive carcinoma from TCGA and METABRIC [57]
All660IHC
FC		BTLA positivity: 15/660 (2.3%)NAPositive case cut-off: ≥ 1 BTLA+ TIL
All BTLA+ TILs also expressed PD-1
According to FC, CD4 and CD8+TILs don’t express BTLA		[58]
TLR9TNBC (Afro-American population)51IHCTLR9 ”low” expression: 27/51 (52.9%)
TLR9 ”high” expression: 22/51 (43.1%)		TLR9 high: no association with recurrence or BCSSVariants of TLR9 gene associated with protection from breast cancer[59]
All and TNBC84 of all subtypes
80 TNBC
350 of all subtypes		RT- PCRIHCmRNA expression in cohort of 84 cases of all subtypes: overexpression in TNBC
IHC expression in sub-group analyses of 38/84 cases of all subtypes: overexpression in 8/38 (21%) and 5/13 (38.5%) TNBC
IHC expression in 80 TNBC cases: 32/80 (40%)
mRNA expression in 350 cases of all subtypes: overexpression in 50/350 (14.3%) and 19/64 (29.7%) TNBC		High mRNA expression: trend to better MFS
High protein expression in 80 TNBC: better MFS		TLR9 also expressed in pre-invasive lesions[60]
All196IHCTLR9 high expression in TNBC: 51/99 (51.5%)TLR9 high expression:
  • All subtypes: no association found
  • TNBC: high expression better BCSS
 [61]
All12RT-PCRTLR9 expression: 12/12 (100%)NA [62]
All124IHCTLR9 positivity: 78/124 (63%)TLR9 positivity:
  • UA: worse PFS
  • MA: not statistically significant
Positive case cut-off: expression > 10% cells
Expression significantly higher in tumors with positive axillary LN metastasis, ER- and advanced stage 		[63]
All74IHCTLR9 expression:
By tumor cells: 73/74 (98.6%)
By fibroblasts 42/74 (58%)		TLR9 positive expression by fibroblasts: better DMFS [64]
All124
116 post-menopausal		RT-PCR
IHC		TLR9 mRNA: overexpression in ER-
TLR9 IHC expression in 116 post-menopausal: 103/116 (88.8%)		 IHC expression higher in ER and PR-[65]
All141IHCTLR9 positivity: 136/141 (98%)TLR9 positivity: worse DMFSHigher expression in ER- and high grade tumors[66]
A2aRNANANANANANANA
CD73All80IHCNACD73 expresion in ER+ cases: no prognostic value
CD73 expression in ER- cases: worse OS		CD73 expression associated with EGFR expression[67]
All136IHCCD73 positivity: 101/136 (74%)CD73 positivity:
UA: better DFS and OS
MA: better DFS, trend to better OS		 [68]
All (Her2 status NA)102IHCCD73 positivity: 9/102 (9%)NAPositive case cut-off: any expression by tumor cells[69]
Not specified74IHCCD73 positivity: 60/74 (81%)NAPositive case cut-off: expression >5% cells[70]
TNBC122IFNATumor cells CD73 expression:
  • UA: worse DFS and OS
  • MA: worse DFS, trend to worse OS
Stromal and immune CD73 expression: no prognostic value		 [71]
All119IHCCD73 positivity: 100/119 (84%)NA [72]
All202Gene expression datasetNAGene-expression database of 1128 cases of all subtypes: worse DFS
Gene-expression of 417 Her2+ cases: worse DFS
Gene-expression of 784 ER+ and 211 TNBC cases: statistically NS trend to worse DFS
METABRIC cohort of 1981 cases of all subtypes: worse DSS		 [73]
All and TNBC6209 all subtypes
59 TNBC		Gene expression datasetNA6209 cases of all subtypes: worse OS for TNBC, no prognostic value for ER+ and Her2+ cases
59 TNBC: worse response to NACT		 [74]
CD39Not specified33FCPT CD39+CD8+ TILs mean frequency: 18.5% +/− 4.3%
Circulating CD8+ T cells: no CD39 expression		NA [75]
All (Her2 NA)11FCNANACD39+CD4+ TILs 28.7+/−5.8% vs 8.2+/−5.9% in normal adjacent tissue
CD39+CD8+ TILs 9+/−3.5% vs 0.4+/−0.3% in normal adjacent tissue		[76]
All50FC
IF
RT-PCR		NANACD39 +Th17 TILs 93.6%
CD39 + TILs Tregs 50.9%
CD39 overexpressed among IL-17Hi tumors		[77]
All3169Gene expression datasetNo CD39 overexpressionNAUse of gene expression dataset Genevestigator v3[31]
Not specified10Gene expression datasetCD39 overexpressed in BC compared to healthy tissueNAMicro-array dataset from Turashvili et al. (BMC Cancer. 2007 Mar 27;7:55.) [78]
Abbreviations: LAG-3, lymphocyte-activation gene 3; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; VISTA, V-domain Ig suppressor of T cell activation; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; GITR, glucocorticoid-induced TNFR-related protein; B7-H3, B7 homolog 3; ICOS, Inducible T-cell costimulator; 4-1BB; CD70, cluster of differentiation 70; BTLA, B- and T-lymphocyte attenuator; TLR9, Toll-like receptor 9; A2aR, A2A adenosine receptor; CD73, cluster of differentiation 73; CD39, cluster of differentiation 39; BC, breast cancer; TNBC, triple-negative breast cancer; Her2, human epidermal growth factor receptor 2; NACT, neo-adjuvant chemotherapy; RT-PCR, reverse transcription polymerase chain reaction; IHC, immunohistochemistry; FC, flow-cytometry; IF, immunofluorescence; mRNA, messenger RNA; TILs, tumor-infiltrating lymphocytes; NA, not assessed; UA, univariate analysis; MA, multivariate analysis; pCR, pathological complete response; RFS, relapse-free survival; OS, overall survival; BCSS, breast cancer specific survival; PD-1, Programmed cell death 1; PD-L1, Programmed death-ligand 1; DFMS, distant-metastasis free survival; MFS, metastasis-free survival; PFS, progression-free survival; DFS, disease-free survival; ER, estrogen receptor; PR, progesterone receptor; NS, non significant; DSS, disease-specific survival; TMA, tissue microarray; Tregs, regulatory T cells; LN, lymph-node; TCGA, the cancer genome atlas; EGFR, epidermal growth factor receptor.
Table
Table 2. Ongoing clinical trials potentially including breast cancer patients for targeting immune-related markers predominantly expressed on T-cells.
Table 2. Ongoing clinical trials potentially including breast cancer patients for targeting immune-related markers predominantly expressed on T-cells.
TargetDrugOther Agent(s)PhaseDiseaseLineNCT IdentifierTrial Status
LAG-3IMP 321
(Eftilagimod)		+ PaclitaxelI/IIAdvanced BC1st lineNCT00349934Completed, published results
[27]
+ PaclitaxelIibHormone positive advanced BC1st lineNCT02614833Recruiting, safety results published [79]
+ PaclitaxelIAdvanced BC (chinese population)1st lineNCT03600090Not yet recruiting
+ standard therapyIAdvanced solid tumorsAny lineNCT03252938Recruiting
MK-4280+/− Pembrolizumab (anti-PD1)IAdvanced solid tumors No standard therapy availableNCT02720068Recruiting
BMS-986016
(Relatlimab)		+/− Nivolumab (anti-PD1)IAdvanced solid tumors No standard therapy availableNCT02966548Recruiting
+ Nivolumab (anti-PD1) and BMS-986205 (IDO1 inhibitor)
Or + Nivolumab (anti-PD1) and Ipilimumab (anti-CTLA4)		I/IIAdvanced solid tumors Any lineNCT03459222Recruiting
REGN3767+/− REGN2810 (anti-PD1)IAdvanced solid tumors No standard therapy availableNCT03005782Recruiting
LAG525
(IMP701)		+/− PDR001 (anti-PD1)I/IIAdvanced solid tumors including TNBC≥ 1 lineNCT02460224Active, not recruiting
Preliminary results published [80]
+/− PDR001 (anti-PD1)
+/− Carboplatin		IIAdvanced TNBC1st or 2nd lineNCT03499899Suspended
+ PDR001 (anti-PD1)
+ NIR178 (A2aR antagonist) or Capmantinib (C-MET inhibitor) or MCS110 (anti-M-CSF) or Canakinumab (anti-IL1)		I/IbTNBC≤ 2 linesNCT03742349Recruiting
TSR-033+ anti-PD1IAdvanced solid tumors No standard therapy availableNCT03250832Recruiting
INCAGN02385NoIAdvanced solid tumors including TNBCNo standard therapy availableNCT03538028Not yet recruiting
Sym022NoIAdvanced solid tumorsNo standard therapy availableNCT03489369Recruiting
+ Sym021 (anti-PD1) or Sym023 (anti-TIM3)IAdvanced solid tumorsNo standard therapy availableNCT03311412Recruiting
MGD013 (Anti-
LAG3 + Anti-PD1)		NoIAdvanced solid tumorsNo standard therapy availableNCT03219268Recruiting
FS118 (Anti-LAG3 + Anti-PDL1)NoIAdvanced solid tumors that progressed on anti-PD1/PDL-1 therapy≥ 1 lineNCT03440437Recruiting
XmAb®22841 (Anti-
LAG3 + Anti-CTLA4)		NoIAdvanced solid tumors including TNBCNo standard therapy availableNCT03849469Not yet recruiting
TIM-3MBG453+/− PDR001 (anti-PD1)I-Ib/IIAdvanced solid tumors (phase I)No standard therapy availableNCT02608268Recruiting
TSR-022NoIAdvanced solid tumors No standard therapy availableNCT02817633Recruiting
+ Carboplatin
+ Nab-paclitaxel
+ TSR-042 (anti-PD1)		IAdvanced solid tumors≤ 1 line (part B)
≤ 4 lines (part A)
NCT03307785Recruiting
LY3321367+/− LY3300054 (anti-PDL1)Ia/IbAdvanced solid tumors No standard therapy availableNCT03099109Recruiting
INCAGN02390NoIAdvanced solid tumors including TNBCNo standard therapy availaibleNCT03652077Recruiting
Sym023NoIAdvanced solid tumors No standard therapy availaibleNCT03489343Recruiting
+ Sym021 (anti-PD1) or Sym022 (anti-LAG3)IAdvanced solid tumorsNo standard therapy availableNCT03311412Recruiting
LY3321367+/− LY3300054 (anti-PDL1)IAdvanced solid tumors Any lineNCT03099109Recruiting
BGB-A425+/− Tislelizumab (anti-PD1) for phase III/IIAdvanced solid tumors No standard therapy availableNCT03744468Recruiting
LY3415244 (Anti-TIM3 + Anti-PDL1)NoIa/IbAdvanced solid tumors Any line (phase Ia)
≥ 1 line with anti-PD1 or anti-PDL1 therapy (phase Ib)		NCT03752177Recruiting
MBG453 + PDR001 (anti-PD1)I/IIAdvanced solid tumors No standard therapy available and no prior anti-PD1/PDL1 therapyNCT02608268Recruiting
VISTACA-170NoIAdvanced solid tumors including TNBCNo standard therapy availaibleNCT02812875Recruiting
TIGITAB154+/− AB122 (anti-PD1)IAdvanced solid tumors No standard therapy availaibleNCT03628677Recruiting
OMP-313M32
(Etigilimab)		+/− Nivolumab (anti-PD1)Ia/IbAdvanced solid tumors No standard therapy availaibleNCT03119428Active, not recruiting
BMS-986207+/− Nivolumab (anti-PD1)I/IIAdvanced solid tumorsNo standard therapy availaibleNCT02913313Recruiting
GITRMK-4166+/− Pembrolizumab (anti-PD1)IAdvanced solid tumors No standard therapy availaibleNCT02132754Active, not recruiting
INCAGN01876+/− Epacadostat (IDO1 inhibitor)
+/− Pembrolizumab (anti-PD1)		I/IIAdvanced solid tumors (phase I)No standard therapy availaibleNCT03277352Active, not recruiting
+/− Nivolumab (anti-PD1)
+/− Ipilimumab (anti-CTLA4)		I/IIAdvanced solid tumors (phase I)No standard therapy availaibleNCT03126110Recruiting
NoI/IIAdvanced solid tumors (phase I)No standard therapy availaibleNCT02697591Recuiting
TRX518+/− Gemcitabine
+/− Pembrolizumab (anti-PD1)
+/− Nivolumab (anti-PD1)		IAdvanced solid tumors (monotherapy and association with Gemcitabine)No standard therapy availaible or indication for GemcitabineNCT02628574Recruiting
NoIAdvanced solid tumors No standard therapy availaibleNCT01239134Recruiting, safety results published [81]
+ Cyclophosphamide and/or Avelumab (anti-PDL1)I/IIAdvanced solid tumors including TNBC and hormone receptor positive refractory BCTNBC: 2nd or 3rd line
Hormone receptor positive BC: ≥ 1 line with aromatase inhibitor 		NCT03861403Not yet recruiting
BMS-986156+/− Nivolumab (anti-PD1)I/IiaAdvanced solid tumors No standard therapy availaibleNCT02598960Active, not recruiting
preliminary results [82]
+/− Nivolumab (anti-PD1)IAdvanced solid tumors ≥ 2 linesNCT03335540Recruiting
GWN323+/− PDR001 (anti-PD1)I/IbAdvanced solid tumors Not specifiedNCT02740270Active, not recruiting
MEDI1873NoIAdvanced solid tumors Not specifiedNCT02583165Completed, no published results
OMP-336B11NoIaAdvanced solid tumors No standard therapy availaibleNCT03295942Active, not recruiting
B7-H3MGA271 (Enoblituzumab)+/− Pembrolizumab (anti-PD1)IAdvanced solid tumors including TNBC No standard therapy availableNCT02475213Active, not recruiting
+ Ipilimumab (anti-CTLA4)IAdvanced solid tumors including TNBC No standard therapy availableNCT02381314Active, not recruiting
MGD009
(Orlotamab)		NoIAdvanced solid tumors including TNBC ≥ 1 prior lineNCT02628535Recruiting
MGA012 (anti-PD1)IAdvanced solid tumors expressing B7-H3No standard therapy availableNCT03406949Recruiting
MGC018+/− MGA012 (anti-PD1)I/IIAdvanced solid tumorsNo standard therapy availableNCT03729596Recruiting
ICOSJTX-2011 +/− Nivolumab (anti-PD1)
+/− Ipilimumab (anti-CTLA4)
+/− Pembrolizumab (anti-PD1)		I/IIAdvanced solid tumors No standard therapy availaibleNCT02904226Recruiting, safety results published [83]
BMS-986226+/− Nivolumab (anti-PD1) or Ipilimumab (anti-CTLA4)I/IIAdvanced solid tumors ≥ 1 prior line NCT03251924Recruiting
4-1BBPF-05082566
(Utolimumab)		+ Trastuzumab – Vinorelbine – Avelumab (anti-PDL1)
+ Trastuzumab – Avelumab (anti-PDL1)		IIAdvanced Her2+ BC≥ 1 prior line with progression under Trastuzumab - PertuzumabNCT03414658Recruiting
Cohort 1: + Trastuzumab – Emtansine
Cohort 2: + Trastuzumab		IBAdvanced Her2+ BCCohort 1: ≥ 1 prior line with taxane and trastuzumab
Cohort 2: ≥ 2 prior lines		NCT03364348Recruiting
+ Avelumab (anti-PDL1)IB/IIAdvanced solid tumors including TNBCAny lineNCT02554812Recruiting
Arm A: + Avelumab (Anti-PD-L1)
Arm C: + Avemulmab (anti-PD-L1) and PF-04518600 (anti-OX40)		I/IIAdvanced solid tumors No strandard therapy availableNCT03217747Recruiting
BMS-663513
(Urelumab)		+/− Nivolumab (anti-PD1)I/IIAdvanced solid tumors Any lineNCT02253992Active, not recruiting
+ SBRT – Nivolumab (anti-PD1)IAdvanced solid tumors Any lineNCT03431948Recruiting
NoIAdvanced solid tumors No strandard therapy availableNCT01471210Completed, preliminary safety results published [84]
+ Nivolumab (anti-PD1)IAdvanced solid tumors No strandard therapy availableNCT02534506Active, not recruiting
+ Nivolumab (anti-PD1)I/IIAdvanced solid tumors No strandard therapy availableNCT03792724Not yet recruiting
PRS-343+ Atezolizumab (anti-PDL1)IBAdvanced solid tumors including Her2+ BC≥ 2nd lineNCT03650348Recruiting
NoIAdvanced solid tumors including Her2+ BCNo strandard therapy availableNCT03330561Recruiting
ADG106NoIAdvanced solid tumorsNo strandard therapy availableNCT03802955Recruiting
NoIAdvanced solid tumorsNo strandard therapy availableNCT03707093Recruiting
CD27/CD70Anti-hCD70 CAR PBL+ Aldeskeukin (IL-2)I/IIAdvanced solid tumors expressing CD70 ≥ 2nd lineNCT02830724Recruiting
ARGX-110
(Cusatuzumab)		NoI/IIAdvanced solid tumors expressing CD70 No standard therapy availableNCT01813539Active, not recruiting
Safety results published [85]
CDX-1127 (Varlilumab)+ ONT-10 (Immunovaccine)IBAdvanced BC≥ 2nd lineNCT02270372Completed, no published results
OX40/OX40LMOXR0916
(Vonlerolizumab)		NoIAdvanced solid tumors No standard therapy availableNCT02219724Active, not recruiting
+ Atezolizumab (anti-PDL1)IBAdvanced solid tumors No standard therapy availableNCT02410512Active, not recruiting
Preliminary safety results published [86]
PF-04518600+ Avelumab (anti-PDL1)
Or + Utolilumab (Anti-4-1BB) and Avelumab (anti-PDL1)
+/− Radiation		I/IIAdvanced solid tumors No standard therapy availableNCT03217747Recruiting
MEDI6383+/− MEDI4736 (anti-PDL1)IAdvanced solid tumors No standard therapy available
≤ 5 prior lines		NCT02221960Completed, no published results
MEDI0562+/− MEDI4736 (anti-PDL1)
Or +/− Tremelilumab (anti-CTLA4)		IAdvanced solid tumors No standard therapy available
≤ 3 prior lines		NCT02705482Active, not recruiting
INCAGN01949NoI/IIAdvanced solid tumors No standard therapy availableNCT02923349Active, not recruiting
+/− Nivolumab (anti-PD1)
+/− Ipilimumab (anti-CTLA4)		I/IIAdvanced solid tumors (phase I)No standard therapy availableNCT03241173Active, not recruiting
GSK3174998 +/− Pembrolizumab (anti-PD1)IAdvanced solid tumors No standard therapy available
≤ 5 prior lines		NCT02528357Recruiting
+ GSK1795091 (TLR4 agonist)IAdvanced solid tumors including BC but not TNBCNo standard therapy availableNCT03447314Recruiting
MEDI6469+ SBRT to liver or lung metastasesI/IIAdvanced BC≥ 1 prior lineNCT01862900Completed, no published results
mRNA 2416NoIAdvanced solid tumors No standard therapy availableNCT03323398Recruiting
BMS-986178+ intra-tumoral SD-101 (TLR9 agonist)IAdvanced solid tumors≥ 1 prior lineNCT03831295Recruiting
+/− Nivolumab (anti-PD1) and/or Ipilimumab (anti-CTLA4)I/IIaAdvanced solid tumors≥ 1 prior lineNCT02737475Recruiting
BTLANANANANANANANA
TLR9IMO-2125
(Tilsotolomid)
Intra-tumoral		NoIbAdvanced solid tumors Any line (previously treated with anti-PDL1 therapy if indicated)NCT03052205Active, not recruiting
Preliminary safety results published [87]
Agatolimod
(CPG 7909; PF-3512676)		+ TrastuzumabI/IIAdvanced Her2+ BC≤ 3 linesNCT00043394Completed, no published results
+ TrastuzumabI/IIAdvanced Her2+ BCNot specifiedNCT00031278Completed, no published results
+ Montanide® ISA-51 (immune modulator)
+ NY-ESO-l protein (therapeutic vaccine)		ILocalised solid tumors Neo-adjuvant or adjuvant chemotherapy authorisedNCT00299728Completed, no published results
+ Montanide ISA 720 (immune modulator)
+ Cyclophosphamide
+ NY-ESO-1-derived Peptides or Protein (therapeutic vaccine)		IAdvanced solid tumors expressing NY-ESO-1≥ 2nd lineNCT00819806Completed, no results published
MGN1703+ Ipilimumab (anti-CTLA4)IAdvanced solid tumors No standard therapy availableNCT02668770Recruiting
SD-101+ BMS 986178 (anti-OX40)IAdvanced solid tumors ≥ 1 prior lineNCT03831295Recruiting
+ Pembrolizumab (anti-PD1)IIStage II or III BCNo prior treatmentNCT01042379Recruiting
Adenosine pathway
A2aRNIR178+/− NZV930 (anti-CD73)
+/− PDR001 (anti-PD1)		I/IBAdvanced solid tumors including TNBCNo standard therapy availableNCT03549000Recruiting
+ PDR001 (anti-PD1) and LAG525 (anti-LAG3)IAdvanced TNBC≤ 2 prior linesNCT03742349Recruiting
AZD4635+/− Durvalumab (Anti-PDL1)IAdvanced solid tumors No standard therapy availableNCT02740985Recruiting
AB928+ AB122 (anti-PD1)IAdvanced solid tumors No standard therapy availableNCT03629756Recruiting
+/− Pegylated liposomal doxorubicinI/IbAdvanced TNBCNo standard therapy availableNCT03719326Recruiting
CPI-444+/− Atezolizumab (anti-PDL1)IAdvanced solid tumors including TNBC≥ 1 and ≤ 5 prior linesNCT02655822Recruiting
+/− CPI-006 (anti-CD73)I/IBAdvanced solid tumors including TNBC≥ 1 and ≤ 5 prior linesNCT03454451Recruiting
CD73SRF373
(NZV930)		+/− PDR001 (anti-PD1)
+/− NIR178 (A2aR antagonist)		I/IBAdvanced solid tumors including TNBCNo standard therapy availableNCT03549000Recruiting
CPI-006+/− CPI-444 (A2aR antagonist)
+/− Pembrolizumab (anti-PD1)		I/IBAdvanced solid tumors including TNBC≥ 1 and ≤ 5 prior linesNCT03454451Recruiting
BMS-986179+/− Nivolumab (anti-PD1)
+/− rHuPH20 (Recombinant human hyaluronidase)		I/IIAAdvanced solid tumors Any lineNCT02754141Recruiting, preliminary results published [88]
MEDI9447
(Oleclumab)		+/− MEDI4736 (anti-PDL1)IAdvanced solid tumors Any lineNCT02503774Recruiting
+ Paclitaxel – Carboplatin – Durvalumab (anti-PDL1)I/IIAdvanced TNBC1st lineNCT03616886Recruiting
NoIAdvanced solid tumors (Japanese population)No standard therapy availableNCT03736473Active, not recruiting
+ NACT
+ pre-operative surgery
+ Durvalumab (anti-PDL1)		IILuminal B BC (neo-adjuvant setting)Neo-adjuvant settingNCT03875573Not yet recruiting
+ Paclitaxel
+ Durvalumab (anti-PDL1)		I/IIAdvanced TNBC1st lineNCT03742102Recruiting
CD39NANANANANANANA
Abbreviations: LAG-3, lymphocyte-activation gene 3; TIM-3, T-cell immunoglobulin and mucin-domain containing-3; VISTA, V-domain Ig suppressor of T cell activation; TIGIT, T-cell immunoreceptor with Ig and ITIM domains; GITR, glucocorticoid-induced TNFR-related protein; B7-H3, B7 homolog 3; ICOS, Inducible T-cell costimulator; 4-1BB; CD27, cluster of differentiation 27; CD70, cluster of differentiation 70; BTLA, B- and T-lymphocyte attenuator; TLR9, Toll-like receptor 9; A2aR, A2A adenosine receptor; CD73, cluster of differentiation 73; CD39, cluster of differentiation 39; PD1, Programmed cell death 1; IDO1, Indoleamine 2, 3-dioxygenase 1; CTLA4, Cytotoxic T-Lymphocyte Associated Protein 4; PDL1, Programmed death-ligand 1, IL-2, Interleukine-2; SBRT, Stereotactic Body Radiation Therapy; NACT, neo-adjuvant chemotherapy; BC, breast cancer; TNBC, triple-negative breast cancer; Her2, human epidermal growth factor receptor 2.
Table
Table 3. Expression and prognostic/predictive value of immune-related markers predominantly expressed by macrophages, NK and dendritic-cells in breast cancer (BC) patients.
Table 3. Expression and prognostic/predictive value of immune-related markers predominantly expressed by macrophages, NK and dendritic-cells in breast cancer (BC) patients.
MarkerBC
Subtype		Number of PatientsMethodPositive/Overexpressing CasesPrognostic/Predictive valueCommentsReference
Macrophage-related
CSF-1/CSF-1RAll581
(301 node-negative, 280 node-positive)		IHCPositive cases:
node-negative 114/301 (38.9%)
node-positive 189/280 (67.5%) 		Positivity in node negative: worse OS (not in node positive patients) [264]
All196IHC
in situ RNA detection		74% CSF-1+ and 58% CSF-1R+ tumorsCSF-1+ tumor cells: poor survivalCSF-1+ tumor cells: more frequent metastases[263]
All572ELISA (circulating CSF1 levels)NAlogCSF1: worse BCCS
high CSF-1: worse outcome in post-menopausal patients		Cut-off: median serum CSF-1 expression[262]
All68IHCNAHigh CSF-1: worse DSSHigh CSF-1R: marginally correlated to worse DSS[261]
CCL2/CCR2All137IHCCCL2+ tumor cells: 30.7% in PTs vs 39.4% in paired recurrences
CCL2+ stromal cells: 18.2% in PTs vs 22.6% in paired recurrences		No correlation Significantly higher CCL2 expression in tumor cells of recurrences (especially the early ones) compared to PTs[267]
All427IHCNAStromal but not epithelial CCL2 expression: worse RFS in basal-like subtypeStromal CCL2 remained an independent factor of worse prognosis in basal-like subtype[268]
All63IHCNACCR2 expression in tumor cells: worse DFS, MFS and OSCCR2 expression in tumor cells and CCL2 expression in stromal cells associated with higher risk of metastasis.
CCR2 expression in tumor cells remained an independent factor of worse MFS		[269]
All151
(135 evaluable)		IHCCCL2 high: 65/135 (48.1%)
CCL2 low: 70/135 (51.9%)		CCL2 high: worse RFSHigh combined CCL2/VEGF expression was independently associated with worse RFS[270]
All3554
(TCGA and kmplot.com)		RNA-seqNAHigh mRNA CCL2 expression: better RFS in basal-like, HER2-enriched and luminal-B subtypes (median cutoff of mRNA expression)No significant association between RFS and expression of CCL2 mRNA in the whole cohort and in luminal-A subtype[271]
CD40All181IHCCytoplasmic tumor cell expression: 53%
Membrane tumor cell expression: 7.7%
Nuclear tumor cell expression: 81%		CD40 cytoplasmic positivity: better OSPositive association of CD40 cytoplasmic expression in HR+ breast tumors[272]
NK cell-related
CD94/NKG2AAll28
(TDLN)		Flow cytometryNANAHigh expression of NKG2A in NK cells of tumor-draining lymph nodes described
NKG2A+ NK cells correlated to locally advanced disease		[273]
NKG2D ligands (MICBAB, ULBP1-5)All677IHCTumor cell expression:
MIC-AB: 50%
ULBP-1: 90%
ULBP-2: 99%
ULBP-3: 100%
ULBP-4: 26%
ULBP-5: 90%		High MIC-AB and ULBP-2 expression better RFSCombined low expression of MIC-AB and ULBP-2 correlated to worse RFS[274]
Dendritic cell-related
IDOAll (Pakistani population)100IHC100% positive
24/100 low IDO (24%)
27/100 medium IDO (27%)
49/100 high IDO (49%)		Medium and high IDO: worse OSIDO expression correlated to TNBC[275]
All203IHC100% positive
108/203 low IDO (53.2%)
95/203 intermediate and high IDO (46.8%)		General population: no difference in OS
ER+ IDO intermediate/high: better OS
Node-positive IDO intermediate/high: better DSS		IDO expression correlated to ER+[276]
All26 primary tumor + TDLN
10 benign lesions		IHCIDO positivity:
PT: 12/26 (46.15%)
TDLN: 19/26 (73.08%)
Benign lesions: 1/10 (10%)		IDO expression: statistically not significant worse OS and TTPIDO expression correlated to advanced stages, lymph-node metastasis and Treg infiltration
No expression in healthy adjacent tissue		[277]
All155IHCStromal positivity (>5%): 49/155 (31%)
Epithelial positivity (>10%) 24/155 (15%)		IDO positivity: better OSIDO positivity correlated to absence of lymph-node metastasis, ER- and TNBC[278]
All242 primary tumor
20 TDLN
19 metastasis		IHCIDO positivity:
PT: 34/242 (14%)
TDLN: 1/20 (5%)
Metastasis: 0/19 (0%)		NAIDO positivity correlated to high grade and TNBC
Co-expression of IDO in 70% of PDL-1+ cases		[279]
All65IHCIDO positivity: 42/65 (64.6%)IDO expression: worse OS and PFS in UA but not MAIDO expression correlated to high grade, lymph-node metastastasis[280]
All54IHCIDO positivity: 27/54 (68.5%)IDO expression: worse response to NACT and statistically not significant worse PFS and OSIDO expression correlated to advanced stages, lymph-node metastasis[281]
All129 PT
10 normal LN
17 metastatic LN		IHCIDO expression:
PT: NA
Normal lymph-nodes 80%
Metastatic lymph nodes 88.2%		NAIDO expression correlated to lymph-node metastasis, ER-, TNBC and PD-1 expression[282]
All54 PT
11 healthy controls		qRT-PCRNANAIDO expression reduced in tumor compared to healthy tissue
IDO expression in tumor correlated to advanced stage		[283]
All46IHCIDO high: 26/46 (56.5%)IDO high: worse response to NACT and worse PFS and OSIDO high correlated to advanced stage and lymph-node metastasis[284]
HR+362IHCIDO expression 276/362 (76.2%)IDO expression: worse OSIDO expression not correlated to clinico-pathological characteristics
IDO expression negatively correlated to B-cell infiltration		[285]
All202IHCNAIDO high (expression by CAFs): worse DSS and MFS [286]
All91 PT
21 benign lesions
10 healthy controls		IHCIDO expression:
PT: 55/91 (60%)
Benign lesions 9/21 (43%)
Healthy controls 2/10 (20%)		NAIDO expression correlated to advanced stage[287]
All85IHCNANAIDO expression correlated to Treg infiltration and lymph-node metastasis[288]
All5IHCIDO expression 5/5 (100%)NA [289]
Abbreviations: CSF-1R, colony-stimulating factor 1 receptor; CSF-1, colony-stimulating factor 1; CCL2, C-C Motif Chemokine Ligand 2; CCR2, C-C Motif Chemokine Receptor 2; IDO, Indoleamine 2,3-dioxygenase; NK-cells, natural-killer cells; CD40, cluster of differentiation 40; CD94, cluster of differentiation 94; NKG2A, NK group member 2A; NKG2D, NK group member 2D; VEGF, vascular endothelial growth factor; IHC, immunohistochemistry; qRT-PCR, quantitative real-time polymerase chain reaction; T-reg, T-regulatory cells; OS, overall survival; PFS, progression-free survival; MFS, metastasis-free survival; RFS, relapse-free survival; TTP, time-to-progression; DSS, disease-specific survival; BCCS, breast cancer-specific survival; PT, primary tumor; NACT, neoadjuvant chemotherapy; PD-1, programmed death 1; TNBC, triple-negative breast cancer; ER, estrogen receptor; HR, hormone receptor; CAFs, cancer-associated fibroblasts; MICBA/B, MHC class I chain-related protein A and B; ULBP1-5, UL binding protein 1-5; LN, lymph node; TDLN, tumor-draining lymph node; NA, not available.
Table
Table 4. Ongoing clinical trials potentially including breast cancer patients for targeting of immune-related markers predominantly expressed on macrophages, NK and dendritic cells.
Table 4. Ongoing clinical trials potentially including breast cancer patients for targeting of immune-related markers predominantly expressed on macrophages, NK and dendritic cells.
TargetDrugOther Agent(s)PhaseDiseaseLineNCT IdentifierTrial Status
TAM-stimulatory markers
CSF-1/CSF-1R
CSF-1R/CSF-1 inhibitorsPLX 3397
(Pexidartinib)		+ EribulinIb/IIMetastatic breast cancer≥ 1 prior lineNCT01596751Active, not recruiting
NoIAdvanced solid tumorsNo standard therapy availableNCT01004861Active, not recruiting
+/− PaclitaxelIbAdvanced solid tumorsNot specifiedNCT01525602Completed, no published results
ARRY-382+/− Pembrolizumab (anti-PD1)Ib/IIAdvanced solid tumors including TNBC (phase Ib)No standard therapy availableNCT02880371Recruiting
NoIAdvanced or metastatic solid tumorsNo standard therapy availableNCT01316822Completed, no published results
BLZ945+/− PDR001 (anti-PD1)IAdvanced solid tumors including TNBCNot specifiedNCT02829723Recruiting
Anti CSF-1R antibodiesLY3022855
(IMC-CS4)		NoIAdvanced BC≥ 1 prior lineNCT02265536Completed, no published results
+ Durvalumab (anti-PDL1) or Tremelimumab (anti-CTLA4)IAdvanced solid tumorsNot specifiedNCT02718911Completed, no published results
NoIAdvanced solid tumorsNo standard therapy availableNCT01346358 Completed, safety results published [290]
RO5509554
(Emactuzumab)		+ Atezolizumab (anti-PDL1)IAdvanced solid tumors including TNBCNot specifiedNCT02323191Recruiting
+/− PaclitaxelIAdvanced solid tumorsNo standard therapy availableNCT01494688 Completed, preliminary safety and activity results published [291]
+ RO7009789 (CD40 agonist)IbAdvanced solid tumors including TNBCNo standard therapy availableNCT02760797Completed, no published results
AMG820NoIAdvanced solid tumorsNot specifiedNCT01444404Completed, no published results
SNDX-6352Phase Ia: SNDX-6352 monotherapy
Phase Ib: + Durvalumab (anti-PDL1)		IAdvanced solid tumors≥ 1 prior line and no standard therapy availableNCT03238027Recruiting
Cabiralizumab (BMS-986227, FPA008)+/− Nivolumab (anti-PD1)IAdvanced malignanciesNo standard therapy availableNCT03158272Recruiting
+ Nivolumab (anti-PD1) and SBRTIAdvanced malignanciesNo standard therapy availableNCT03431948Recruiting
PD 0360324 (M-CSF mAb)+ Avelumab (anti-PDL1)Ib/IIAdvanced solid tumors including TNBCNo standard therapy availableNCT02554812Recruiting
CCL2/CCR2
CCR2 antagonistPF-04136309+ Avelumab (anti-PDL1)
+Utomilumab (anti-4-1BB)		Ib/IIAdvanced solid tumors including TNBCNo standard therapy availableNCT02554812Recruiting
CD47 – SIRPα
Anti-CD47 antibodiesHu5F9-G4+ Cetuximab (anti-EGFR)Ib/IIAdvanced solid tumors including BC (phase Ib)≥ 1 prior lineNCT02953782Recruiting
+Avelumab (anti-PDL1)IbAdvanced solid tumorsNot specified NCT03558139Recruiting
CC-90002NoIAdvanced solid tumorsNo standard therapy availableNCT02367196Recruiting
IBI188NoIaAdvanced solid tumorsNo standard therapy availableNCT03763149Recruiting
NoIAdvanced solid tumorsNo standard therapy availableNCT03717103Recruiting
AO-176NoIAdvanced solid tumorsNo standard therapy availableNCT03834948Recruiting
SRF231NoI/IbAdvanced solid tumorsNo standard therapy availableNCT03512340Recruiting
SIRPα-IgG1-FcTTI-621
(intra-tumoral injection)		+/− PD1/PDL1 InhibitorIAdvanced solid tumors with percutaneously accessible lesionsNo standard therapy available NCT02890368Recruiting
ALX148+/− Trastuzumab or Pembrolizumab (anti-PD1) or Rituximab (anti-CD20)IAdvanced solid tumorsNo standard therapy availableNCT03013218Recruiting, preliminary safety results published [292]
TAM-inhibitory markers
CD40 (agonists)CP-870,893NoIAdvanced solid tumors No standard therapy availableNCT02225002Completed, no published results
NoIAdvanced solid tumorsPatients who had clinical benefit following a single infusion of CP-870, 893NCT02157831Completed
RO7009789
Selicrelumab		+ Atezolizumab (anti PDL1)IbAdvanced solid tumorsNo standard therapy availableNCT02304393 Recruiting
+ Emactuzumab (anti-CSF-1R)IAdvanced solid tumors including TNBCNo standard therapy availableNCT02760797Completed, no published results
+ Vanucizumab (anti-VEGF-A and angiopoietin-2)IMetastatic solid tumorsNot specifiedNCT02665416Recruiting
ADC-1013
(intra-tumoral or intra-venous injection)		NoIAdvanced solid tumorsNot specified NCT02379741Completed, no published results
JNJ-64457107NoIAdvanced solid tumorsNot specifiedNCT0282909Recruiting
TLR7
(agonists)		Imiquimod+ Cyclophosphamide and RadiotherapyI/IIAdvanced BC with skin metastasesAny lineNCT01421017Completed, no published results
NK cell-inhibitory markers
CD94/
NKG2A		IPH2201+ Durvalumab (anti-PDL1)I/IIAdvanced solid tumorsAny lineNCT02671435Recruiting
KIR familyLirilumab
(anti-KIR2DL1,2,3 antibody)		+Nivolumab (anti-PD1)
Or + Nivolumab (anti-PD1) and Ipilimumab (anti-CTLA4)		IAdvanced and/or metastatic solid tumorsNot specifiedNCT03203876Active, not recruiting
+Nivolumab (anti-PD1)I/IIAdvanced solid tumors≥ 1 and ≤ 5 prior linesNCT01714739Active, not recruiting
IDO
Small-molecule inhibitor of IDO-1Epacadostat
(INCB024360)		+ INCB01158
(arginase inhibitor)
+/− Pembrolizumab (anti-PD1)		I/IIAdvanced solid tumors No standard therapy availableNCT03361228Active, not recruiting
+ Pembrolizumab (anti-PD1)I/IIAdvanced or metastatic solid tumors including TNBC (phase I)≥ 1 prior lineNCT02178722Active, not recruiting
Preliminary safety and efficacy results published [293]
+ Sirolimus (mTOR inhinitor)IAdvanced solid tumors≥ 1 prior line and no standard therapy availableNCT03217669Recruiting
+Nivolumab (anti-PD1) and Ipilimumab (anti-CTLA4) (group A)
+ Nivolumab (anti-PD1) + lirilumab (anti-KIR) (group B)		I/IIAdvanced solid tumorsNo standard therapy available (phase I)
≥ 1 prior line (phase II)		NCT03347123Active, not recruiting
+ Durvalumab (anti-PDL1)I/IIAdvanced solid tumors≥ 1 prior lineNCT02318277Active, not recruiting
+ Pembrolizumab (anti-PD1)
And mFOLFOX6
Or (anti-PD1) Gemcitabine and
Nab-Paclitaxel
Or Carboplatin and Paclitaxel
Or Pemetrexed, and Platinium agent
Or Cyclophosphamide
Or Gemcitabine and Platinium agent
Or Platinium agent and 5-Fu		I/IIAdvanced solid tumorsNot specifiedNCT03085914Active, not recruiting
+/− Pembrolizumab (anti-PD1)
Or +/−Pembrolizumab (anti-PD1) and Carboplatin or Cisplatin and Paclitaxel
Or +/− Pembrolizumab (anti-PD1) and Carboplatin and Paclitaxel		IAdvanced solid tumors (Japanese population)No standard therapy availableNCT02862457Active, not recruiting
Preliminary safety and efficacy results published [294]
+ Pembrolizumab (anti-PD1) and Azacitidine (DNA methyl transferase inhibitor)
Or + INCB057643 (BET inhibitor) + Pembrolizumab (anti-PD1)
Or + INCB059872 (LSD1 inhibitor) and Pembrolizumab (anti-PD1)		I/IIAdvanced solid tumorsNo standard therapy availableNCT02959437Active, not recruiting
NoIAdvanced solid tumorsNo standard therapy availableNCT01195311Completed, safety results published [295]
+ Pembrolizumab (anti-PD1) and INCAGN01876 (anti-GITR)I/IIAdvanced solid tumorsNo standard therapy avaialbleNCT03277352Active, not recruiting
+ Itacitinib (JAK inhibitor)IAdvanced solid tumors including TNBCNo standard therapy availableNCT02559492Active, not recruiting
NoIbResectable metastatic solid tumorsEligible for surgical resection and no standard therapy availableNCT03471286Recruiting
GDC-0919
(navoximod)		+ Atezolizumab (anti-PD-1)IbAdvanced solid tumors≥ 1 prior lineNCT02471846Active, not recruiting
NLG802NoIAdvanced solid tumorsNot specifiedNCT03164603Recruiting
Abbreviations: TAM, tumor-associated macrophages; CSF-1R, colony-stimulating factor 1 receptor; CSF-1, colony-stimulating factor 1; PD-1, programmed death 1; PD-L1, programmed death ligand 1; SBRT, stereotactic body radiation therapy; CCL2, C-C Motif Chemokine Ligand 2; CCR2, C-C Motif Chemokine Receptor 2; CD47, cluster of differentiation 47; SIRPα, signal regulatory protein alpha; IDO, Indoleamine 2,3-dioxygenase; TLR7, toll-like receptor 7; NK-cells, natural-killer cells; CD40, cluster of differentiation 40; CD94, cluster of differentiation 94; KIR, Killer Immunoglobin Receptors; NKG2A, NK group member 2A; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; KIR2DL1, Killer cell immunoglobulin-like receptor 2DL1; JAK, janus kinase; mTOR: mammalian target of rapamycin; BC, breast cancer; TNBC, triple-negative breast cancer; LSD1, lysine specific demethylase 1; BET, Bromodomain and Extra-Terminal motif; EGFR, epidermal growth factor receptor; VEGF-A, vascular endothelial growth factor A.
Table
Table 5. Overview of immune-related markers’ characteristics including origin of expression and their role in anti-tumor immunity.
Table 5. Overview of immune-related markers’ characteristics including origin of expression and their role in anti-tumor immunity.
MarkerTypes of Cells ExpressedFunction on Anti-tumor Immunity
LAG-3Effector T-cells, Tregs, NK-cells, B-cells, dendritic cells (DC)Co-inhibitory
TIM-3CD8+, CD4+ T helper 1 cells (Th1 cells), Tregs, NK cells, DC, monocytes, macrophagesCo-inhibitory
VISTACD8+, CD4+ T-cells, Tregs, NK cells, DC, monocytes, macrophages, granulocytesCo-inhibitory
TIGITEffector, memory, follicular helper (Tfh) T-cells, Tregs, NK-cellsCo-inhibitory
GITRT-cellsCo-stimulatory
B7-H3T-cells, antigen-presenting cells (APC), NK-cellsCo-stimulatory
Co-inhibitory
ICOST-cellsCo-stimulatory
Co-inhibitory
4-1BBEffector, helper T-cells, Tregs, B-cells, NK-cells, DC, neutrophils, eosinophils,
mast cells, monocytes, macrophages		Co-stimulatory
CD27T-cells, B-cells, NK-cellsCo-stimulatory
OX40Tregs, neutrophils, NK-cells and NKT-cells, CD4+ and CD8+ T-cells (upon TCR stimulation)Co-stimulatory
BTLAT-cells, B-cells, Tfh cells, macrophages, DC, NKT-cells, NK-cellsCo-inhibitory
A2aRT-cells, NKT-cells, B-cells, monocytes, macrophages, DC, NK-cells, mast cells, eosinophils, plateletsCo-inhibitory
CD73B-cells, CD8+, CD4+ T-cells, Tregs, neutrophils, MDSC, monocytes, macrophages, DC, NK-cells, endothelial cells, cancer cellsCo-inhibitory
CD39Platelets, endothelial cells, cancer cellsCo-inhibitory
CCR2Monocytes, macrophagesCo-inhibitory
CD47Cancer cellsCo-inhibitory
CD40APC, macrophagesCo-stimulatory
CD94/NKG2ANK-cells, CD8+ T-cellsCo-inhibitory
NKG2DNK-cellsCo-stimulatory
IDOCancer cells, stromal dendritic-like cells, myoepithelial cellsCo-inhibitory

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MDPI and ACS Style

Chrétien, S.; Zerdes, I.; Bergh, J.; Matikas, A.; Foukakis, T. Beyond PD-1/PD-L1 Inhibition: What the Future Holds for Breast Cancer Immunotherapy. Cancers 2019, 11, 628. https://doi.org/10.3390/cancers11050628

AMA Style

Chrétien S, Zerdes I, Bergh J, Matikas A, Foukakis T. Beyond PD-1/PD-L1 Inhibition: What the Future Holds for Breast Cancer Immunotherapy. Cancers. 2019; 11(5):628. https://doi.org/10.3390/cancers11050628

Chicago/Turabian Style

Chrétien, Sebastian, Ioannis Zerdes, Jonas Bergh, Alexios Matikas, and Theodoros Foukakis. 2019. "Beyond PD-1/PD-L1 Inhibition: What the Future Holds for Breast Cancer Immunotherapy" Cancers 11, no. 5: 628. https://doi.org/10.3390/cancers11050628

APA Style

Chrétien, S., Zerdes, I., Bergh, J., Matikas, A., & Foukakis, T. (2019). Beyond PD-1/PD-L1 Inhibition: What the Future Holds for Breast Cancer Immunotherapy. Cancers, 11(5), 628. https://doi.org/10.3390/cancers11050628

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