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NK/ILCs in Tumors

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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 October 2020) | Viewed by 54809

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Prof. Dr. Lorenzo Moretta

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Tumor Immunology, Pediatric Hospital Bambino Gesù, Viale San Paolo, 15, 00146 Rome, Italy
Interests: human NK cells; human ILC; tumor microenvironment (human)
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Dear Colleagues,

Innate lymphoid cells (ILCs) were identified over ten years ago as a novel lymphoid cell family belonging to the innate immune system and found to be developmentally related to natural killer (NK) cells. Unlike NK cells, ILCs are non-cytolytic and predominantly located in barrier tissues, and have been classified into four distinct subsets according to the typical set of cytokines that they release (ILC1, ILC2, ILC3, and LTi—collectively referred to as “helper” ILCs). They are involved in innate defense against different pathogens and in tissue homeostasis/repair. On the other hand, they may play a role in the pathogenesis of immunological disorders. The possible involvement of ILCs in tumor immunity or, rather, in tumor development, progression, and spreading/metastasis remains uncertain. Indeed, a number of contradictory data have been reported showing either the promoting or suppressive activity of ILCs in different tumor models. Thus, any attempt to exploit ILCs in tumor therapy should carefully take into consideration several points, namely 1) the main effects of cytokines released by a given ILC subset on tumor cells and on cells of the tumor microenvironment (TM), 2) the effect of the TM on NK/ILC effector functions, and 3) the high degree of plasticity, characteristic of both immature and mature ILCs . In view of the favorable or harmful effects of ILCs on tumor growth, tumor therapy may be based on targeting or rather harnessing a given ILC subset. In addition, given the ILC plasticity, modulating agents could adapt their functional profile towards a favorable antitumor activity.

This Special Issue deals with the pathophysiological aspects of NK/ILCs with a major focus on solid tumors and leukemia. It outlines our current knowledges spanning from the well-established role of NK cells in the cure of otherwise lethal acute leukemia to the still unclear involvement of different helper ILCs in the control of solid tumors. The promising exploitation of CAR-NK cells redirected to tumor surface antigens as well as the use of checkpoint inhibitors targeting inhibitory pathways regulating NK cell function are also discussed in depth.

Prof. Dr. Lorenzo Moretta
Guest Editor

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Keywords

NK cells
innate lymphoid cells (ILCs)
innate defenses against tumors
NK receptors
natural cytotoxicity receptors (NCRs)
killer Ig-like receptors (KIRs)
inhibitory checkpoints
tumor microenvironment (TM)
ILC plasticity
immunotherapy
haplo-identical hemopoietic stem cell transplantation (HSCT)
CAR-NK cells

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Published Papers (13 papers)

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Research

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16 pages, 2888 KiB

Open AccessEditor’s ChoiceArticle

Type 2 Innate Lymphoid Cells Protect against Colorectal Cancer Progression and Predict Improved Patient Survival

by Qiutong Huang, Nicolas Jacquelot, Adele Preaudet, Soroor Hediyeh-zadeh, Fernando Souza-Fonseca-Guimaraes, Andrew N. J. McKenzie, Philip M. Hansbro, Melissa J. Davis, Lisa A. Mielke, Tracy L. Putoczki and Gabrielle T. Belz

Cancers 2021, 13(3), 559; https://doi.org/10.3390/cancers13030559 - 1 Feb 2021

Cited by 33 | Viewed by 5119

Abstract

Chronic inflammation of the gastrointestinal (GI) tract contributes to colorectal cancer (CRC) progression. While the role of adaptive T cells in CRC is now well established, the role of innate immune cells, specifically innate lymphoid cells (ILCs), is not well understood. To define the role of ILCs in CRC we employed complementary heterotopic and chemically-induced CRC mouse models. We discovered that ILCs were abundant in CRC tumours and contributed to anti-tumour immunity. We focused on ILC2 and showed that ILC2-deficient mice developed a higher tumour burden compared with littermate wild-type controls. We generated an ILC2 gene signature and using machine learning models revealed that CRC patients with a high intratumor ILC2 gene signature had a favourable clinical prognosis. Collectively, our results highlight a critical role for ILC2 in CRC, suggesting a potential new avenue to improve clinical outcomes through ILC2-agonist based therapeutic approaches. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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20 pages, 7284 KiB

Open AccessArticle

EZH1/2 Inhibitors Favor ILC3 Development from Human HSPC-CD34⁺ Cells

by Laura Damele, Adriana Amaro, Alberto Serio, Silvia Luchetti, Ulrich Pfeffer, Maria Cristina Mingari and Chiara Vitale

Cancers 2021, 13(2), 319; https://doi.org/10.3390/cancers13020319 - 16 Jan 2021

Cited by 9 | Viewed by 3255

Abstract

The dysregulation of epigenetic modifications has a well-established role in the development and progression of hematological malignancies and of solid tumors. In this context, EZH1/2 inhibitors have been designed to interfere with EZH1/2 enzymes involved in histone methylation (e.g., H3K27me3), leading to tumor growth arrest or the restoration of tumor suppressor gene transcription. However, these compounds also affect normal hematopoiesis, interfering with self-renewal and differentiation of CD34⁺-Hematopoietic Stem/Progenitor Cells (HSPC), and, in turn, could modulate the generation of potential anti-tumor effector lymphocytes. Given the important role of NK cells in the immune surveillance of tumors, it would be useful to understand whether epigenetic drugs can modulate NK cell differentiation and functional maturation. CD34⁺-HSPC were cultured in the absence or in the presence of the EZH1/2 inhibitor UNC1999 and EZH2 inhibitor GSK126. Our results show that UNC1999 and GSK126 increased CD56⁺ cell proliferation compared to the control condition. However, UNC1999 and GSK 126 favored the proliferation of no-cytotoxic CD56⁺ILC3, according to the early expression of the AHR and ROR-γt transcription factors. Our results describe novel epigenetic mechanisms involved in the modulation of NK cell maturation that may provide new tools for designing NK cell-based immunotherapy. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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22 pages, 3940 KiB

Open AccessArticle

Wilms’ Tumor Primary Cells Display Potent Immunoregulatory Properties on NK Cells and Macrophages

by Piera Filomena Fiore, Paola Vacca, Nicola Tumino, Francesca Besi, Andrea Pelosi, Enrico Munari, Marcella Marconi, Ignazio Caruana, Vito Pistoia, Lorenzo Moretta and Bruno Azzarone

Cancers 2021, 13(2), 224; https://doi.org/10.3390/cancers13020224 - 9 Jan 2021

Cited by 12 | Viewed by 2826

Abstract

The immune response plays a crucial defensive role in cancer growth and metastasis and is a promising target in different tumors. The role of the immune system in Wilm’s Tumor (WT), a common pediatric renal malignancy, is still to be explored. The characterization of the immune environment in WT could allow the identification of new therapeutic strategies for targeting possible inhibitory mechanisms and/or lowering toxicity of the current treatments. In this study, we stabilized four WT primary cultures expressing either a blastematous (CD56⁺/CD133⁻) or an epithelial (CD56⁻/CD133⁺) phenotype and investigated their interactions with innate immune cells, namely NK cells and monocytes. We show that cytokine-activated NK cells efficiently kill WT cells. However, after co-culture with WT primary cells, NK cells displayed an impaired cytotoxic activity, decreased production of IFNγ and expression of CD107a, DNAM-1 and NKp30. Analysis of the effects of the interaction between WT cells and monocytes revealed their polarization towards alternatively activated macrophages (M2) that, in turn, further impaired NK cell functions. In conclusion, we show that both WT blastematous and epithelial components may contribute directly and indirectly to a tumor immunosuppressive microenvironment that is likely to play a role in tumor progression. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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18 pages, 3034 KiB

Open AccessArticle

Centromeric KIR AA Individuals Harbor Particular KIR Alleles Conferring Beneficial NK Cell Features with Implications in Haplo-Identical Hematopoietic Stem Cell Transplantation

by Léa Dubreuil, Bercelin Maniangou, Patrice Chevallier, Agnès Quéméner, Nolwenn Legrand, Marie C. Béné, Catherine Willem, Gaëlle David, Mehdi Alizadeh, Dhon Roméo Makanga, Anne Cesbron, Ketevan Gendzekhadze, Katia Gagne and Christelle Retière

Cancers 2020, 12(12), 3595; https://doi.org/10.3390/cancers12123595 - 1 Dec 2020

Cited by 12 | Viewed by 3818

Abstract

We have recently shown a broad disparity of Natural Killer (NK) cell responses against leukemia highlighting good and bad responders resting on the Killer cell Immunoglobulin-like Receptors (KIR) and HLA genetics. In this study, we deeply studied KIR2D allele expression, HLA-C recognition and functional effect on NK cells in 108 blood donors in combining high-resolution KIR allele typing and multicolor flow cytometry. The KIR2DL1*003 allotype is associated with centromeric (cen) AA motif and confers the highest NK cell frequency, expression level and strength of KIR/HLA-C interactions compared to the KIR2DL1*002 and KIR2DL1*004 allotypes respectively associated with cenAB and BB motifs. KIR2DL2*001 and *003 allotypes negatively affect the frequency of KIR2DL1⁺ and KIR2DL3⁺ NK cells. Altogether, our data suggest that cenAA individuals display more efficient KIR2DL alleles (L1*003 and L3*001) to mount a consistent frequency of KIR2DL⁺ NK cells and to confer an effective NK cell responsiveness. The transposition of our in vitro observations in the T-replete haplo-identical HSCT context led us to observe that cenAA HSC grafts limit significantly the incidence of relapse in patients with myeloid diseases after T-replete haplo-identical HSCT. As NK cells are crucial in HSCT reconstitution, one could expect that the consideration of KIR2DL1/2/3 allelic polymorphism could help to refine scores used for HSC donor selection. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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21 pages, 1990 KiB

Open AccessArticle

Phenotypic and Functional Characterization of NK Cells in αβT-Cell and B-Cell Depleted Haplo-HSCT to Cure Pediatric Patients with Acute Leukemia

by Raffaella Meazza, Michela Falco, Fabrizio Loiacono, Paolo Canevali, Mariella Della Chiesa, Alice Bertaina, Daria Pagliara, Pietro Merli, Valentina Indio, Federica Galaverna, Mattia Algeri, Francesca Moretta, Natalia Colomar-Carando, Letizia Muccio, Simona Sivori, Andrea Pession, Maria Cristina Mingari, Lorenzo Moretta, Alessandro Moretta, Franco Locatelli and Daniela Pende Show full author list Hide full author list

Cancers 2020, 12(8), 2187; https://doi.org/10.3390/cancers12082187 - 5 Aug 2020

Cited by 18 | Viewed by 3934

Abstract

NK cells can exert remarkable graft-versus-leukemia (GvL) effect in HLA-haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Here, we dissected the NK-cell repertoire of 80 pediatric acute leukemia patients previously reported to have an excellent clinical outcome after αβT/B-depleted haplo-HSCT. This graft manipulation strategy allows the co-infusion of mature immune cells, mainly NK and γδT cells, and hematopoietic stem cells (HSCs). To promote NK-cell based antileukemia activity, 36/80 patients were transplanted with an NK alloreactive donor, defined according to the KIR/KIR-Ligand mismatch in the graft-versus-host direction. The analysis of the reconstituted NK-cell repertoire in these patients showed relatively high proportions of mature and functional KIR⁺NKG2A⁻CD57⁺ NK cells, including the alloreactive NK cell subset, one month after HSCT. Thus, the NK cells adoptively transfused with the graft persist as a mature source of effector cells while new NK cells differentiate from the donor HSCs. Notably, the alloreactive NK cell subset was endowed with the highest anti-leukemia activity and its size in the reconstituted repertoire could be influenced by human cytomegalovirus (HCMV) reactivation. While the phenotypic pattern of donor NK cells did not impact on post-transplant HCMV reactivation, in the recipients, HCMV infection/reactivation fostered a more differentiated NK-cell phenotype. In this cohort, no significant correlation between differentiated NK cells and relapse-free survival was observed. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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Review

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15 pages, 7544 KiB

Open AccessReview

Killing the Invaders: NK Cell Impact in Tumors and Anti-Tumor Therapy

by Martina Molgora, Victor S. Cortez and Marco Colonna

Cancers 2021, 13(4), 595; https://doi.org/10.3390/cancers13040595 - 3 Feb 2021

Cited by 21 | Viewed by 4555

Abstract

Natural Killer cells belong to group 1 innate lymphoid cells, which also includes ILC1s. NK/ILC1s are highly heterogeneous cell types showing distinct phenotypes across tissues and conditions. NK cells have long been described as innate lymphocytes able to directly and rapidly kill tumor cells without antigen-restriction. Different mechanisms were shown to modulate NK cell activation and tumor resistance, mainly based on cytokine stimulation and receptor–ligand interactions, and several strategies have been developed to target NK cells in tumor immunotherapy to promote NK cell function and overcome tumor evasion. The characterization of ILC1 distinct phenotype and function and the specific role in tumors still needs further investigation and will be essential to better understand the impact of innate lymphoid cells in tumors. Here, we review key aspects of NK cell biology that are relevant in tumor immune surveillance, emphasizing the most recent findings in the field. We describe the novel therapeutical strategies that have been developed in tumor immunotherapy targeting NK cells, and we summarize some recent findings related to NK cell/ILC1 transition in tumor models. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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15 pages, 783 KiB

Open AccessReview

Unraveling the Role of Innate Lymphoid Cells in Acute Myeloid Leukemia

by Matthew R. Lordo, Steven D. Scoville, Akul Goel, Jianhua Yu, Aharon G. Freud, Michael A. Caligiuri and Bethany L. Mundy-Bosse

Cancers 2021, 13(2), 320; https://doi.org/10.3390/cancers13020320 - 17 Jan 2021

Cited by 8 | Viewed by 3543

Abstract

Over the past 50 years, few therapeutic advances have been made in treating acute myeloid leukemia (AML), an aggressive form of blood cancer, despite vast improvements in our ability to classify the disease. Emerging evidence suggests the immune system is important in controlling AML progression and in determining prognosis. Natural killer (NK) cells are important cytotoxic effector cells of the innate lymphoid cell (ILC) family that have been shown to have potent anti-leukemic functions. Recent studies are now revealing impairment or dysregulation of other ILCs in various types of cancers, including AML, which limits the effectiveness of NK cells in controlling cancer progression. NK cell development and function are inhibited in AML patients, which results in worse clinical outcomes; however, the specific roles of other ILC populations in AML are just now beginning to be unraveled. In this review, we summarize what is known about the role of ILC populations in AML. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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31 pages, 1446 KiB

Open AccessReview

Prospects for NK Cell Therapy of Sarcoma

by Mieszko Lachota, Marianna Vincenti, Magdalena Winiarska, Kjetil Boye, Radosław Zagożdżon and Karl-Johan Malmberg

Cancers 2020, 12(12), 3719; https://doi.org/10.3390/cancers12123719 - 11 Dec 2020

Cited by 14 | Viewed by 5229

Abstract

Natural killer (NK) cells are innate lymphoid cells with potent antitumor activity. One of the most NK cell cytotoxicity-sensitive tumor types is sarcoma, an aggressive mesenchyme-derived neoplasm. While a combination of radical surgery and radio- and chemotherapy can successfully control local disease, patients with advanced sarcomas remain refractory to current treatment regimens, calling for novel therapeutic strategies. There is accumulating evidence for NK cell-mediated immunosurveillance of sarcoma cells during all stages of the disease, highlighting the potential of using NK cells as a therapeutic tool. However, sarcomas display multiple immunoevasion mechanisms that can suppress NK cell function leading to an uncontrolled tumor outgrowth. Here, we review the current evidence for NK cells’ role in immune surveillance of sarcoma during disease initiation, promotion, progression, and metastasis, as well as the molecular mechanisms behind sarcoma-mediated NK cell suppression. Further, we apply this basic understanding of NK–sarcoma crosstalk in order to identify and summarize the most promising candidates for NK cell-based sarcoma immunotherapy. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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20 pages, 961 KiB

Open AccessReview

Role of the Main Non HLA-Specific Activating NK Receptors in Pancreatic, Colorectal and Gastric Tumors Surveillance

by Elisa Ferretti, Simona Carlomagno, Silvia Pesce, Letizia Muccio, Valentina Obino, Marco Greppi, Agnese Solari, Chiara Setti, Emanuela Marcenaro, Mariella Della Chiesa and Simona Sivori

Cancers 2020, 12(12), 3705; https://doi.org/10.3390/cancers12123705 - 10 Dec 2020

Cited by 11 | Viewed by 3657

Abstract

Human NK cells can control tumor growth and metastatic spread thanks to their powerful cytolytic activity which relies on the expression of an array of activating receptors. Natural cytotoxicity receptors (NCRs) NKG2D and DNAM-1 are those non-HLA-specific activating NK receptors that are mainly involved in sensing tumor transformation by the recognition of different ligands, often stress-induced molecules, on the surface of cancer cells. Tumors display several mechanisms aimed at dampening/evading NK-mediated responses, a relevant fraction of which is based on the downregulation of the expression of activating receptors and/or their ligands. In this review, we summarize the role of the main non-HLA-specific activating NK receptors, NCRs, NKG2D and DNAM-1, in controlling tumor growth and metastatic spread in solid malignancies affecting the gastrointestinal tract with high incidence in the world population, i.e., pancreatic ductal adenocarcinoma (PDAC), colorectal cancer (CRC), and gastric cancer (GC), also describing the phenotypic and functional alterations induced on NK cells by their tumor microenvironment. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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25 pages, 801 KiB

Open AccessReview

Cancer Immunotherapy by Blocking Immune Checkpoints on Innate Lymphocytes

by Silvia Pesce, Sara Trabanelli, Clara Di Vito, Marco Greppi, Valentina Obino, Fabio Guolo, Paola Minetto, Matteo Bozzo, Michela Calvi, Elisa Zaghi, Simona Candiani, Roberto Massimo Lemoli, Camilla Jandus, Domenico Mavilio and Emanuela Marcenaro

Cancers 2020, 12(12), 3504; https://doi.org/10.3390/cancers12123504 - 25 Nov 2020

Cited by 35 | Viewed by 4371

Abstract

Immune checkpoints refer to a plethora of inhibitory pathways of the immune system that play a crucial role in maintaining self-tolerance and in tuning the duration and amplitude of physiological immune responses to minimize collateral tissue damages. The breakdown of this delicate balance leads to pathological conditions, including cancer. Indeed, tumor cells can develop multiple mechanisms to escape from immune system defense, including the activation of immune checkpoint pathways. The development of monoclonal antibodies, targeting inhibitory immune checkpoints, has provided an immense breakthrough in cancer therapy. Immune checkpoint inhibitors (ICI), initially developed to reverse functional exhaustion in T cells, recently emerged as important actors in natural killer (NK)-cell-based immunotherapy. Moreover, the discovery that also helper innate lymphoid cells (ILCs) express inhibitory immune checkpoints, suggests that these molecules might be targeted on ILCs, to modulate their functions in the tumor microenvironment. Recently, other strategies to achieve immune checkpoint blockade have been developed, including miRNA exploiting systems. Herein, we provide an overview of the current knowledge on inhibitory immune checkpoints on NK cells and ILCs and we discuss how to target these innate lymphocytes by ICI in both solid tumors and hematological malignancies. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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21 pages, 835 KiB

Open AccessReview

Group 2 Innate Lymphoid Cells: A Double-Edged Sword in Cancer?

by Enrico Maggi, Irene Veneziani, Lorenzo Moretta, Lorenzo Cosmi and Francesco Annunziato

Cancers 2020, 12(11), 3452; https://doi.org/10.3390/cancers12113452 - 20 Nov 2020

Cited by 19 | Viewed by 2849

Abstract

Group 2 Innate Lymphoid Cells (ILC2s) belong to the family of helper ILCs which provide host defense against infectious agents, participate in inflammatory responses and mediate lymphoid organogenesis and tissue repair, mainly at the skin and mucosal level. Based on their transcriptional, phenotypic and functional profile, ILC2s mirror the features of the adaptive CD4+ Th2 cell subset, both contributing to the so-called type 2 immune response. Similar to other ILCs, ILC2s are rapidly activated by signals deriving from tissue and/or other tissue-resident immune cells. The biologic activity of ILCs needs to be tightly regulated in order to prevent them from contributing to severe inflammation and damage in several organs. Indeed, ILC2s display both enhancing and regulatory roles in several pathophysiological conditions, including tumors. In this review, we summarize the actual knowledge about ILC2s ability to induce or impair a protective immune response, their pro- or antitumor activity in murine models, human (children and adults) pathologies and the potential strategies to improve cancer immunotherapy by exploiting the features of ILC2s. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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20 pages, 704 KiB

Open AccessFeature PaperReview

The Immune Checkpoint PD-1 in Natural Killer Cells: Expression, Function and Targeting in Tumour Immunotherapy

by Linda Quatrini, Francesca Romana Mariotti, Enrico Munari, Nicola Tumino, Paola Vacca and Lorenzo Moretta

Cancers 2020, 12(11), 3285; https://doi.org/10.3390/cancers12113285 - 6 Nov 2020

Cited by 100 | Viewed by 6340

Abstract

In the last years, immunotherapy with antibodies against programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) has shown remarkable efficacy in the treatment of different types of tumours, representing a true revolution in oncology. While its efficacy has initially been attributed only to unleashing T cell responses, responsivity to PD-1/PD-L1 blockade was observed in some tumours with low Human Leukocyte Antigen (HLA) I expression and increasing evidence has revealed PD-1 surface expression and inhibitory function also in natural killer (NK) cells. Thus, the contribution of anti-PD-1/PD-L1 therapy to the recovery of NK cell anti-tumour response has recently been appreciated. Here, we summarize the studies investigating PD-1 expression and function in NK cells, together with the limitations and perspectives of immunotherapies. A better understanding of checkpoint biology is needed to design next-generation therapeutic strategies and to improve the clinical protocols of current therapies. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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27 pages, 824 KiB

Open AccessReview

Natural Killer Cells in Immunotherapy: Are We Nearly There?

by Mireia Bachiller, Anthony M. Battram, Lorena Perez-Amill and Beatriz Martín-Antonio

Cancers 2020, 12(11), 3139; https://doi.org/10.3390/cancers12113139 - 27 Oct 2020

Cited by 17 | Viewed by 4053

Abstract

Natural killer (NK) cells are potent anti-tumor and anti-microbial cells of our innate immune system. They are equipped with a vast array of receptors that recognize tumor cells and other pathogens. The innate immune activity of NK cells develops faster than the adaptive one performed by T cells, and studies suggest an important immunoregulatory role for each population against the other. The association, observed in acute myeloid leukemia patients receiving haploidentical killer-immunoglobulin-like-receptor-mismatched NK cells, with induction of complete remission was the determinant to begin an increasing number of clinical studies administering NK cells for the treatment of cancer patients. Unfortunately, even though transfused NK cells demonstrated safety, their observed efficacy was poor. In recent years, novel studies have emerged, combining NK cells with other immunotherapeutic agents, such as monoclonal antibodies, which might improve clinical efficacy. Moreover, genetically-modified NK cells aimed at arming NK cells with better efficacy and persistence have appeared as another option. Here, we review novel pre-clinical and clinical studies published in the last five years administering NK cells as a monotherapy and combined with other agents, and we also review chimeric antigen receptor-modified NK cells for the treatment of cancer patients. We then describe studies regarding the role of NK cells as anti-microbial effectors, as lessons that we could learn and apply in immunotherapy applications of NK cells; these studies highlight an important immunoregulatory role performed between T cells and NK cells that should be considered when designing immunotherapeutic strategies. Lastly, we highlight novel strategies that could be combined with NK cell immunotherapy to improve their targeting, activity, and persistence. Full article

(This article belongs to the Special Issue NK/ILCs in Tumors)

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