Tumor Microenvironment may Shape the Function and Phenotype of NK Cells Through the Induction of Split Anergy and Generation of Regulatory NK Cells

Lung cancer remains the leading cause of cancer death worldwide despite the significant progress made by immune checkpoint inhibitors, including programmed death receptor-1 (PD1)/PD ligand 1 (PDL1)-blockade therapy. PD1/PDL1−blockade has achieved unprecedented tumor regression in some patients with advanced lung cancer. However, the majority of patients fail to respond to PD1/PDL1 inhibitors. The high rate of therapy non-response results from insufficient PDL1 expression on most patients’ tumors and the presence of further immunosuppressive mechanisms in the tumor microenvironment. Here, we sensitize non-responding tumors from patients with lung cancer to PD1-blockade therapy using highly cytotoxic expanded natural killer (NK) cells. We uncover that NK cells expanded from patients with lung cancer dismantle the immunosuppressive tumor microenvironment by maintaining strong antitumor activity against both PDL1+ and PDL1− patient tumors. In the process, through a contact-independent mechanism involving interferon γ, expanded NK cells rescued tumor killing by exhausted endogenous TILs and upregulated the tumor proportion score of PDL1 across patient tumors. In contrast, unexpanded NK cells, which are susceptible to tumor-induced immunosuppression, had no effect on tumor PDL1. As a result, combined treatment of expanded NK cells and PD1-blockade resulted in robust synergistic tumor destruction of initially non-responding patient tumors. Thus, expanded NK cells may overcome the critical roadblocks to extending the prodigious benefits of PD1-blockade therapy to more patients with lung cancer and other tumor types.

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H2O2 production within tumor microenvironment inversely correlated with infiltration of CD56dim NK cells in gastric and esophageal cancer: possible mechanisms of NK cell dysfunction

Cancer Immunology Immunotherapy ◽

10.1007/s00262-011-1082-7 ◽

2011 ◽

Vol 60 (12) ◽

pp. 1801-1810 ◽

Cited By ~ 27

Author(s):

Shinichirou Izawa ◽

Koji Kono ◽

Kousaku Mimura ◽

Yoshihiko Kawaguchi ◽

Mitsuaki Watanabe ◽

...

Keyword(s):

Esophageal Cancer ◽

Tumor Microenvironment ◽

Nk Cells ◽

Nk Cell ◽

H2o2 Production ◽

Cell Dysfunction

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799 Neoantigen-cytokine-chemokine multifunctional natural killer cell engager for immunotherapy of solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-sitc2021.799 ◽

2021 ◽

Vol 9 (Suppl 3) ◽

pp. A834-A834

Author(s):

Xue Yao ◽

Sandro Matosevic

Keyword(s):

Tumor Microenvironment ◽

Cell Therapy ◽

Nk Cells ◽

Natural Killer ◽

Solid Tumors ◽

Tumor Cells ◽

Nk Cell ◽

Killer Cell ◽

Nk Cell Therapy

BackgroundThe effectiveness of natural killer (NK) cell-based immunotherapy against solid tumors is limited by the lack of specific antigens and the immunosuppressive tumor microenvironment (TME). Glioblastoma multiforme (GBM) is one such heavily immunosuppressive tumor that has been particularly hard to target and remains without a viable treatment. The development of novel approaches to enhance the efficacy of NK cells against GBM is urgently needed. NK cell engagers (NKCE) have been developed to enhance the efficacy of NK cell therapy.MethodsTo improve the clinical efficacy of NK cell therapy, we are developing a new generation of multi-specific killer engagers, which consists of a neoantigen-targeting moiety, together with cytokine and chemokine-producing domains. Neoantigens are new antigens formed specifically in tumor cells due to genome mutations, making them highly specific tools to target tumor cells. Our engager has been designed to target Wilms' tumor-1 (WT-1), a highly specific antigen overexpressed in GBM among other solid tumors. This is done through the generation of an scFv specific targeting the complex of WT-1126-134/HLA-A*02:01 on the surface of GBM. On the NK cell side, the engager is designed to target the activating receptor NKp46. Incorporation of the cytokine IL-15 within the engager supports the maturation, persistence, and expansion of NK cells in vivo while favoring their proliferation and survival in the tumor microenvironment. Additionally, our data indicated that the chemokine CXCL10 plays an important role in the infiltration of NK cells into GBM, however, GBM tumors produce low levels of this chemokine. Incorporation of a CXCL10-producing function into our engager supports intratumoral NK cell trafficking by promoting, through their synthetic production, increased levels of CXCL10 locally in the tumor microenvironment.ResultsCollectively, this has resulted in a novel multifunctional NK cell engager, combining neoantigen-cytokine-chemokine elements fused to an activating domain-specific to NK cells, and we have investigated its ability to support and enhance NK cell-mediated cytotoxicity against solid tumors in vitro and in vivo against patient-derived GBM models. The multi-specific engager shows both high tumor specificity, as well as the ability to overcome NK cell dysfunction encountered in the GBM TME.ConclusionsWe hypothesize that taking advantage of our multi-functional engager, NK cells will exhibit superior ex vivo expansion, infiltration, and antitumor activity in the treatment of GBM and other solid tumors.

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Natural Killer Cells and Dendritic Cells: Expanding Clinical Relevance in the Non-Small Cell Lung Cancer (NSCLC) Tumor Microenvironment

Cancers ◽

10.3390/cancers13164037 ◽

2021 ◽

Vol 13 (16) ◽

pp. 4037

Author(s):

Pankaj Ahluwalia ◽

Meenakshi Ahluwalia ◽

Ashis K. Mondal ◽

Nikhil S. Sahajpal ◽

Vamsi Kota ◽

...

Keyword(s):

Lung Cancer ◽

Dendritic Cells ◽

Tumor Microenvironment ◽

Small Cell Lung Cancer ◽

Nk Cells ◽

Natural Killer ◽

Cell Lung Cancer ◽

Immune Cells ◽

Small Cell ◽

Small Cell Lung

Non-small cell lung cancer (NSCLC) is a major subtype of lung cancer that accounts for almost 85% of lung cancer cases worldwide. Although recent advances in chemotherapy, radiotherapy, and immunotherapy have helped in the clinical management of these patients, the survival rate in advanced stages remains dismal. Furthermore, there is a critical lack of accurate prognostic and stratification markers for emerging immunotherapies. To harness immune response modalities for therapeutic benefits, a detailed understanding of the immune cells in the complex tumor microenvironment (TME) is required. Among the diverse immune cells, natural killer (NK cells) and dendritic cells (DCs) have generated tremendous interest in the scientific community. NK cells play a critical role in tumor immunosurveillance by directly killing malignant cells. DCs link innate and adaptive immune systems by cross-presenting the antigens to T cells. The presence of an immunosuppressive milieu in tumors can lead to inactivation and poor functioning of NK cells and DCs, which results in an adverse outcome for many cancer patients, including those with NSCLC. Recently, clinical intervention using modified NK cells and DCs have shown encouraging response in advanced NSCLC patients. Herein, we will discuss prognostic and predictive aspects of NK cells and DC cells with an emphasis on NSCLC. Additionally, the discussion will extend to potential strategies that seek to enhance the anti-tumor functionality of NK cells and DCs.

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IM-03 IMMUNOLOGICAL SUBTYPES OF GLIOBLASTOMA BASED ON TUMOR INFILTRATING CELLS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.052 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii12-ii12

Author(s):

Kushihara Yoshihiro ◽

Syota Tanaka ◽

Erika Yamasawa ◽

Tsukasa Koike ◽

Taijun Hana ◽

...

Keyword(s):

Principal Component Analysis ◽

T Cell ◽

Tumor Microenvironment ◽

Nk Cells ◽

Principal Component ◽

Component Analysis ◽

Gene Set ◽

Significant Difference

Abstract To discover novel biological targets in glioblastoma, genomic and immunological analysis were performed using The Cancer Genome Atlas (TCGA) data set. The RNA-seq data of 156 primary glioblastoma cases were subjected to CIBERSORT to detect tumor infiltrating cell fractions. Principal component analysis was performed on this data to detect factors that strongly contribute to the first principal component, and hierarchical clustering was performed. Survival curves were compared for each of the derived clusters. Finally, Gene Set Enrichment Analysis (GSEA) using HALLMARK Gene Set was performed. In the principal component analysis, we detected seven factors (NK cells resting, T cell regulatory, NK cells activated, Macrophage type 0, T cell gamma delta, Macrophage type 2, Macrophage type 1) which strongly contribute to the first principal component. Based on these seven factors, hierarchical cluster analysis resulted in T cell regulatory (Treg), Macrophage type 0 (M0), Macrophage type 2 (M2) and Macrophage type 1 (M1) clusters. There was no significant difference between these groups in CD8 T cell. M2 and M1 clusters displayed better OS with a significant difference. TNFA signaling via NFκB in Treg group, IFNα response, IFNγ response and ALLOGRAFT response in M2 group, G2M CHECKPOINT, GLYCOLYSIS, WNTβ catenin signaling, MITOTIC SPINDLE and TGFβ signaling in M1 group were upregulated. In conclusion, tumor microenvironment of glioblastoma can be divided into 4 immunological subtypes, Treg, M0, M1, and M2. Because of the contribution of innate immunity for shaping the tumor microenvironment of glioblastoma, immunotherapies targeting these innate immune cells are anticipated.

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Hitting More Birds with a Stone: Impact of TGF-β on ILC Activity in Cancer

Journal of Clinical Medicine ◽

10.3390/jcm9010143 ◽

2020 ◽

Vol 9 (1) ◽

pp. 143 ◽

Cited By ~ 6

Author(s):

Cinzia Fionda ◽

Helena Stabile ◽

Cristina Cerboni ◽

Alessandra Soriani ◽

Angela Gismondi ◽

...

Keyword(s):

Tumor Microenvironment ◽

Nk Cells ◽

Cancer Cells ◽

Nk Cell ◽

Critical Role ◽

Cell Activity ◽

Lymphoid Cells ◽

Receptor Expression ◽

Nk Cell Activity ◽

Group I

Transforming growth factor (TGF)-β is a central immunosuppressive cytokine within tumor microenvironment inhibiting the expansion and function of major cellular components of adaptive and innate immune system. Among them, compelling evidence has demonstrated that TGF-β is a key regulator of natural killer (NK) cells, innate lymphoid cells (ILCs) with a critical role in immunosurveillance against different kinds of cancer cells. A TGF-β rich tumor microenvironment blocks NK cell activity at multiple levels. This immunosuppressive factor exerts direct regulatory effects on NK cells including inhibition of cytokine production, alteration of activating/inhibitory receptor expression, and promotion of the conversion into non cytotoxic group I ILC (ILC1). Concomitantly, TGF-β can render tumor cells less susceptible to NK cell-mediated recognition and lysis. Indeed, accumulating evidence suggest that changes in levels of NKG2D ligands, mainly MICA, as well as an increase of immune checkpoint inhibitors (e.g., PD-L1) and other inhibitory ligands on cancer cells significantly contribute to TGF-β-mediated suppression of NK cell activity. Here, we will take into consideration two major mechanisms underlying the negative regulation of ILC function by TGF-β in cancer. First, we will address how TGF-β impacts the balance of signals governing NK cell activity. Second, we will review recent advances on the role of this cytokine in driving ILC plasticity in cancer. Finally, we will discuss how the development of therapeutic approaches blocking TGF-β may reverse the suppression of host immune surveillance and improve anti-tumor NK cell response in the clinic.

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The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity

Cancers ◽

10.3390/cancers12123542 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3542

Author(s):

Joanna Domagala ◽

Mieszko Lachota ◽

Marta Klopotowska ◽

Agnieszka Graczyk-Jarzynka ◽

Antoni Domagala ◽

...

Keyword(s):

Tumor Microenvironment ◽

Nk Cells ◽

Molecular Mechanisms ◽

Cell Function ◽

Nk Cell ◽

Metabolic Changes ◽

Immune Effector ◽

Effector Cells ◽

Immune Effector Cells ◽

Almost All

NK cells have unique capabilities of recognition and destruction of tumor cells, without the requirement for prior immunization of the host. Maintaining tolerance to healthy cells makes them an attractive therapeutic tool for almost all types of cancer. Unfortunately, metabolic changes associated with malignant transformation and tumor progression lead to immunosuppression within the tumor microenvironment, which in turn limits the efficacy of various immunotherapies. In this review, we provide a brief description of the metabolic changes characteristic for the tumor microenvironment. Both tumor and tumor-associated cells produce and secrete factors that directly or indirectly prevent NK cell cytotoxicity. Here, we depict the molecular mechanisms responsible for the inhibition of immune effector cells by metabolic factors. Finally, we summarize the strategies to enhance NK cell function for the treatment of tumors.

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