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Immunotherapy of Triple-Negative Breast Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (15 November 2022) | Viewed by 37162

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Dr. Claudia De Lorenzo

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Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80134 Napoli, Italy
Interests: biochemistry; antibodies; fusion proteins; immunoconjugates; bi-specific antibodies; phage display; immunobiotechnology; breast cancer; cancer immunotherapy; cardioncology; signal transduction
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Dr. Laura Cerchia

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Institute of Experimental Endocrinology and Oncology “G. Salvatore” National Research Council (IEOS-CNR), 80131 Naples, Italy
Interests: nucleic acid aptamer; SELEX technology; tumor markers; targeted therapy; targeted drug delivery; cancer theranostics; cancer cell biology and signaling; chemotherapy resistance; tumor microenvironment; TNBC
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Triple-Negative Breast Cancer (TNBC), which accounts for ~15% of breast cancers, is defined by the absence of estrogen and progesterone receptors and by the lack of epidermal growth factor receptor 2. Management of TNBC is still challenging because of its biological/clinical heterogeneity, aggressive behavior and limited targeted treatment options. The absence of well-defined biomarkers renders chemotherapy the main treatment for TNBC patients. However, chemotherapy has had limited success due to scarce bioavailability, severe systemic side effects and drug resistance. Therefore, improved therapies are urgently needed. TNBC expresses higher levels of programmed cell death-ligand 1 (PD-L1) compared to other breast cancers, providing the rationale for the recently approved immunotherapy with the anti-PD-L1 Atezolizumab plus nab-paclitaxel chemotherapy for patients with unresectable locally advanced or metastatic PD-L1-positive TNBCs. Furthermore, because of the significant role of the immune system in TNBC, ongoing clinical studies are exploring the treatment effectiveness of immunotherapy combined with chemotherapeutic drugs and/or various targeting agents.

This Special Issue invites original research articles and timely reviews on all aspects regarding immunotherapy of TNBC, highlighting problems, solutions and future directions in the development of new therapeutic approaches.

Prof. Dr. Claudia De Lorenzo
Dr. Laura Cerchia
Guest Editors

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Keywords

immunotherapy biomarkers
immune checkpoint inhibitors
immunomodulatory antibodies
tumor-infiltrating lymphocytes
immunotherapy and combination treatments
Bi-specific antibodies
mechanisms of triple-negative breast cancer drug resistance
novel immunotherapy trials
immunoconjugate development

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Published Papers (9 papers)

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Research

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22 pages, 3329 KiB

Open AccessArticle

The Microtubule Destabilizer Eribulin Synergizes with STING Agonists to Promote Antitumor Efficacy in Triple-Negative Breast Cancer Models

by Leila Takahashi-Ruiz, Charles S. Fermaintt, Nancy J. Wilkinson, Peter Y. W. Chan, Susan L. Mooberry and April L. Risinger

Cancers 2022, 14(23), 5962; https://doi.org/10.3390/cancers14235962 - 2 Dec 2022

Cited by 10 | Viewed by 2941

Abstract

Eribulin is a microtubule destabilizer used in the treatment of triple-negative breast cancer (TNBC). Eribulin and other microtubule targeted drugs, such as the taxanes, have shared antimitotic effects, but differ in their mechanism of microtubule disruption, leading to diverse effects on cellular signaling and trafficking. Herein, we demonstrate that eribulin is unique from paclitaxel in its ability to enhance expression of the immunogenic cytokine interferon beta (IFNβ) in combination with STING agonists in both immune cells and TNBC models, including profound synergism with ADU-S100 and E7766, which are currently undergoing clinical trials. The mechanism by which eribulin enhances STING signaling is downstream of microtubule disruption and independent of the eribulin-dependent release of mitochondrial DNA. Eribulin did not override the requirement of ER exit for STING activation and did not inhibit subsequent STING degradation; however, eribulin significantly enhanced IRF3 phosphorylation and IFNβ production downstream of the RNA sensing pathway that converges on this transcription factor. Additionally, we found that eribulin enhanced the population of activated CD4⁺ T-cells in vivo when combined with either a STING agonist or tumor, demonstrating the ability to function as an immune adjuvant. We further interrogated the combination of eribulin with ADU-S100 in the MMTV-PyVT spontaneous murine mammary tumor model where we observed significant antitumor efficacy with combination treatment. Together, our findings demonstrate that microtubule targeted chemotherapeutics have distinct immunological effects and that eribulin’s ability to enhance innate immune sensing pathways supports its use in combination with immunotherapies, such as STING agonists, for the more effective treatment of TNBC and other malignancies. Full article

(This article belongs to the Special Issue Immunotherapy of Triple-Negative Breast Cancer)

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17 pages, 2520 KiB

Open AccessArticle

New Insights on the Role of Anti-PD-L1 and Anti-CTLA-4 mAbs on Different Lymphocytes Subpopulations in TNBC

by Rosa Rapuano Lembo, Lorenzo Manna, Guendalina Froechlich, Emanuele Sasso, Margherita Passariello and Claudia De Lorenzo

Cancers 2022, 14(21), 5289; https://doi.org/10.3390/cancers14215289 - 27 Oct 2022

Cited by 5 | Viewed by 2109

Abstract

Antibody-based cancer immunotherapy includes monoclonals against immune checkpoints (ICs), to modulate specific T cell responses against cancer. NK cells are a newly emerging target for immune checkpoint receptor inhibition in cancer immunotherapy, as ICs are also expressed on NK cells in various cancers. The latter cells are becoming attractive targets for cancer immunotherapy, as they are effector cells similar to CTLs, exerting natural cytotoxicity against primary tumor cells and metastasis, and they are able to distinguish tumor cells from healthy ones, leading to more specific anti-tumor cytotoxicity and reduced off-target effects. Thus, we decided to test the effects on isolated NK cells and T cell subpopulations of novel immunomodulatory mAbs, recently generated in our lab, in comparison with those in clinical use, such as ipilimumab and atezolizumab. Interestingly, we found that the novel anti-CTLA-4 (ID-1) and anti-PD-L1 (PD-L1_1) antibodies are able to induce NK cell activation and exert anti-tumor effects on TNBC cells co-cultured with NK cells more efficiently than the clinically validated ones, either when used as single agents or in combinatorial treatments. On the other hand, ipilimumab was found to be more effective in activating T cells with respect to ID-1. These findings indicate that antibodies targeting different epitopes can have differential effects on different lymphocytes subpopulations and that novel combinations of mAbs could be suitable for therapeutic approaches aimed at activating not only T cells but also NK cells, especially for tumors lacking MHC. Full article

(This article belongs to the Special Issue Immunotherapy of Triple-Negative Breast Cancer)

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28 pages, 5164 KiB

Open AccessArticle

Inflammation-Driven Regulation of PD-L1 and PD-L2, and Their Cross-Interactions with Protective Soluble TNFα Receptors in Human Triple-Negative Breast Cancer

by Tamir Baram, Nino Oren, Nofar Erlichman, Tsipi Meshel and Adit Ben-Baruch

Cancers 2022, 14(14), 3513; https://doi.org/10.3390/cancers14143513 - 19 Jul 2022

Cited by 3 | Viewed by 3214

Abstract

Pro-inflammatory cytokines play key roles in elevating cancer progression in triple-negative breast cancer (TNBC). We demonstrate that specific combinations between TNFα, IL-1β and IFNγ up-regulated the proportion of human TNBC cells co-expressing the inhibitory immune checkpoints PD-L1 and PD-L2: TNFα + IL-1β in MDA-MB-231 cells and IFNγ + IL-1β in BT-549 cells; in the latter cells, the process depended entirely on STAT1 activation, with no involvement of p65 (CRISPR-Cas9 experiments). Highly significant associations between the pro-inflammatory cytokines and PD-L1/PD-L2 expression were revealed in the TCGA dataset of basal-like breast cancer patients. In parallel, we found that the pro-inflammatory cytokines regulated the expression of the soluble receptors of tumor necrosis factor α (TNFα), namely sTNFR1 and sTNFR2; moreover, we revealed that sTNFR1 and sTNFR2 serve as anti-metastatic and protective factors in TNBC, reducing the TNFα-induced production of inflammatory pro-metastatic chemokines (CXCL8, CXCL1, CCL5) by TNBC cells. Importantly, we found that in the context of inflammatory stimulation and also without exposure to pro-inflammatory cytokines, elevated levels of PD-L1 have down-regulated the production of anti-tumor sTNFR1 and sTNFR2. These findings suggest that in addition to its immune-suppressive activities, PD-L1 may promote disease course in TNBC by inhibiting the protective effects of sTNFR1 and sTNFR2. Full article

(This article belongs to the Special Issue Immunotherapy of Triple-Negative Breast Cancer)

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14 pages, 997 KiB

Open AccessArticle

Prognostic Impact of High Baseline Stromal Tumor-Infiltrating Lymphocytes in the Absence of Pathologic Complete Response in Early-Stage Triple-Negative Breast Cancer

by Nour Abuhadra, Ryan Sun, Jennifer K. Litton, Gaiane M. Rauch, Clinton Yam, Jeffrey T. Chang, Sahil Seth, Roland Bassett, Jr., Bora Lim, Alastair M. Thompson, Elizabeth Mittendorf, Beatriz E. Adrada, Senthil Damodaran, Jason White, Elizabeth Ravenberg, Rosalind Candelaria, Banu Arun, Naoto T. Ueno, Lumarie Santiago, Sadia Saleem, Sausan Abouharb, Rashmi K. Murthy, Nuhad Ibrahim, Aysegul A. Sahin, Vicente Valero, William Fraser Symmans, Debu Tripathy, Stacy Moulder and Lei Huo Show full author list Hide full author list

Cancers 2022, 14(5), 1323; https://doi.org/10.3390/cancers14051323 - 4 Mar 2022

Cited by 9 | Viewed by 3083

Abstract

High stromal tumor-infiltrating lymphocytes (sTILs) are associated with an improved pathologic complete response (pCR) and survival in triple-negative breast cancer (TNBC). We hypothesized that high baseline sTILs would have a favorable prognostic impact in TNBC patients without a pCR after neoadjuvant chemotherapy (NACT). In this prospective NACT study, pretreatment biopsies from 318 patients with early-stage TNBC were evaluated for sTILs. Recursive partitioning analysis (RPA) was applied to search for the sTIL cutoff best associated with a pCR. With ≥20% sTILs identified as the optimal cutoff, 33% patients had high sTILs (pCR rate 64%) and 67% had low sTILs (pCR rate 29%). Patients were stratified according to the sTIL cutoff (low vs. high) and response to NACT (pCR vs. residual disease (RD)). The primary endpoint was event-free survival (EFS), with hazard ratios calculated using the Cox proportional hazards regression model and the 3-year restricted mean survival time (RMST) as primary measures. Within the high-sTIL group, EFS was better in patients with a pCR compared with those with RD (HR 0.05; 95% CI 0.01–0.39; p = 0.004). The difference in the 3-year RMST for EFS between the two groups was 5.6 months (95% CI 2.3–8.8; p = 0.001). However, among patients with RD, EFS was not significantly different between those with high sTILs and those with low sTILs (p = 0.7). RNA-seq analysis predicted more CD8+ T cells in the high-sTIL group with favorable EFS compared with the high-sTIL group with unfavorable EFS. This study did not demonstrate that high baseline sTILs confer a benefit in EFS in the absence of a pCR. Full article

(This article belongs to the Special Issue Immunotherapy of Triple-Negative Breast Cancer)

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17 pages, 3332 KiB

Open AccessArticle

Novel Combinations of Human Immunomodulatory mAbs Lacking Cardiotoxic Effects for Therapy of TNBC

by Cinzia Vetrei, Margherita Passariello, Guendalina Froechlich, Rosa Rapuano Lembo, Emanuele Sasso, Nicola Zambrano and Claudia De Lorenzo

Cancers 2022, 14(1), 121; https://doi.org/10.3390/cancers14010121 - 27 Dec 2021

Cited by 9 | Viewed by 3165

Abstract

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer characterized by a higher mortality rate among breast cancer subtypes. Poly(ADP-ribose) polymerase (PARP) inhibitors are used in clinics to treat a subgroup of TNBC patients, but other targeted therapies are urgently needed. Programmed death-ligand 1 (PD-L1), involved in tumor immune escape, was recently identified as a target for TNBC; accordingly, the anti-PD-L1 monoclonal antibody (mAb), atezolizumab, has been approved by FDA in combination with Paclitaxel for the therapy of metastatic TNBC. Here, we tested novel combinations of fully human immunomodulatory mAbs, including anti-PD-L1 mAbs generated in our laboratory and atezolizumab, on TNBC and other tumor cell lines. We evaluated their anti-tumor efficacy when used as single agents or in combinatorial treatments with anti-CTLA-4 mAbs in in vitro co-cultures of hPBMCs with tumor cells, by measuring tumor cell lysis and IL-2 and IFNγ cytokines secretion by lymphocytes. In parallel, by using co-cultures of hPBMCs and cardiomyocytes, we analyzed the potential cardiotoxic adverse side effects of the same antibody treatments by measuring the cardiac cell lysis and the secretion of pro-inflammatory cytokines. We identified novel combinations of immunomodulatory mAbs endowed with more potent anti-cancer activity on TNBC and lower cardiotoxic side effects than the combination of atezolizumab and ipilimumab. Full article

(This article belongs to the Special Issue Immunotherapy of Triple-Negative Breast Cancer)

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Review

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17 pages, 2551 KiB

Open AccessReview

Aptamer-Based Strategies to Boost Immunotherapy in TNBC

by Lisa Agnello, Annachiara d’Argenio, Roberto Nilo, Monica Fedele, Simona Camorani and Laura Cerchia

Cancers 2023, 15(7), 2010; https://doi.org/10.3390/cancers15072010 - 28 Mar 2023

Cited by 8 | Viewed by 2765

Abstract

The immune system (IS) may play a crucial role in preventing tumor development and progression, leading, over the last years, to the development of effective cancer immunotherapies. Nevertheless, immune evasion, the capability of tumors to circumvent destructive host immunity, remains one of the main obstacles to overcome for maximizing treatment success. In this context, promising strategies aimed at reshaping the tumor immune microenvironment and promoting antitumor immunity are rapidly emerging. Triple-negative breast cancer (TNBC), an aggressive breast cancer subtype with poor outcomes, is highly immunogenic, suggesting immunotherapy is a viable strategy. As evidence of this, already, two immunotherapies have recently become the standard of care for patients with PD-L1 expressing tumors, which, however, represent a low percentage of patients, making more active immunotherapeutic approaches necessary. Aptamers are short, highly structured, single-stranded oligonucleotides that bind to their protein targets at high affinity and specificity. They are used for therapeutic purposes in the same way as monoclonal antibodies; thus, various aptamer-based strategies are being actively explored to stimulate the IS’s response against cancer cells. The aim of this review is to discuss the potential of the recently reported aptamer-based approaches to boost the IS to fight TNBC. Full article

(This article belongs to the Special Issue Immunotherapy of Triple-Negative Breast Cancer)

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28 pages, 1054 KiB

Open AccessEditor’s ChoiceReview

Immunotherapy for Triple-Negative Breast Cancer: Combination Strategies to Improve Outcome

by Liying Li, Fan Zhang, Zhenyu Liu and Zhimin Fan

Cancers 2023, 15(1), 321; https://doi.org/10.3390/cancers15010321 - 3 Jan 2023

Cited by 40 | Viewed by 8004

Abstract

Due to the absence of hormone receptor (both estrogen receptors and progesterone receptors) along with human epidermal growth factor receptor 2 (HER-2) amplification, the treatment of triple-negative breast cancer (TNBC) cannot benefit from endocrine or anti-HER-2 therapy. For a long time, chemotherapy was the only systemic treatment for TNBC. Due to the lack of effective treatment options, the prognosis for TNBC is extremely poor. The successful application of immune checkpoint inhibitors (ICIs) launched the era of immunotherapy in TNBC. However, the current findings show modest efficacy of programmed cell death- (ligand) 1 (PD-(L)1) inhibitors monotherapy and only a small proportion of patients can benefit from this approach. Based on the basic principles of immunotherapy and the characteristics of the tumor immune microenvironment (TIME) in TNBC, immune combination therapy is expected to further enhance the efficacy and expand the beneficiary population of patients. Given the diversity of drugs that can be combined, it is important to select effective biomarkers to identify the target population. Moreover, the side effects associated with the combination of multiple drugs should also be considered. Full article

(This article belongs to the Special Issue Immunotherapy of Triple-Negative Breast Cancer)

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27 pages, 2409 KiB

Open AccessReview

Mechanisms and Strategies to Overcome PD-1/PD-L1 Blockade Resistance in Triple-Negative Breast Cancer

by Xingyu Chen, Lixiang Feng, Yujing Huang, Yi Wu and Na Xie

Cancers 2023, 15(1), 104; https://doi.org/10.3390/cancers15010104 - 23 Dec 2022

Cited by 23 | Viewed by 6383

Abstract

Triple-negative breast cancer (TNBC) is characterized by a high rate of systemic metastasis, insensitivity to conventional treatment and susceptibility to drug resistance, resulting in a poor patient prognosis. The immune checkpoint inhibitors (ICIs) represented by antibodies of programmed death receptor 1 (PD-1) and programmed death receptor ligand 1 (PD-L1) have provided new therapeutic options for TNBC. However, the efficacy of PD-1/PD-L1 blockade monotherapy is suboptimal immune response, which may be caused by reduced antigen presentation, immunosuppressive tumor microenvironment, interplay with other immune checkpoints and aberrant activation of oncological signaling in tumor cells. Therefore, to improve the sensitivity of TNBC to ICIs, suitable patients are selected based on reliable predictive markers and treated with a combination of ICIs with other therapies such as chemotherapy, radiotherapy, targeted therapy, oncologic virus and neoantigen-based therapies. This review discusses the current mechanisms underlying the resistance of TNBC to PD-1/PD-L1 inhibitors, the potential biomarkers for predicting the efficacy of anti-PD-1/PD-L1 immunotherapy and recent advances in the combination therapies to increase response rates, the depth of remission and the durability of the benefit of TNBC to ICIs. Full article

(This article belongs to the Special Issue Immunotherapy of Triple-Negative Breast Cancer)

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16 pages, 822 KiB

Open AccessReview

Natural Blockers of PD-1/PD-L1 Interaction for the Immunotherapy of Triple-Negative Breast Cancer-Brain Metastasis

by Maryam Nakhjavani and Sarah Shigdar

Cancers 2022, 14(24), 6258; https://doi.org/10.3390/cancers14246258 - 19 Dec 2022

Cited by 4 | Viewed by 3858

Abstract

The limited treatment options for triple-negative breast cancer with brain metastasis (TNBC-BM) have left the door of further drug development for these patients wide open. Although immunotherapy via monoclonal antibodies has shown some promising results in several cancers including TNBC, it cannot be considered the most effective treatment for brain metastasis. This is due to the protective role of the blood–brain barrier (BBB) which limits the entrance of most drugs, especially the bulky ones such as antibodies, to the brain. For a drug to traverse the BBB via passive diffusion, various physicochemical properties should be considered. Since natural medicine has been a key inspiration for the development of the majority of current medicines, in this paper, we review several naturally-derived molecules which have the potential for immunotherapy via blocking the interaction of programmed cell death protein-1 (PD-1) and its ligand, PD-L1. The mechanism of action, physicochemical properties and pharmacokinetics of these molecules and their theoretical potential to be used for the treatment of TNBC-BM are discussed. Full article

(This article belongs to the Special Issue Immunotherapy of Triple-Negative Breast Cancer)

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