NKG2D signaling in cancer immunosurveillance

López‐Soto, Alejandro; Huergo-Zapico, Leticia; Acebes-Huerta, Andrea; Villa-Álvarez, Mónica; González, Segundo

doi:10.1002/ijc.28775

Cited by 112 publications

(81 citation statements)

References 154 publications

(164 reference statements)

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“…NKG2D is a receptor for MICA/B and ULBP1-6 ligands. 17,18 DNAM-1 is a receptor for poliovirus receptor (PVR, CD155) and Nectin-2 (CD112). 19,20 HLA-B associated transcript 3 (BAT-3) and B7-H6 bind to NKp30; 21 and mixed-lineage leukemia-5 (MLL5) protein has recently been identified as a ligand for NKp44.…”

Section: Introductionmentioning

confidence: 99%

Drug-induced hyperploidy stimulates an antitumor NK cell response mediated by NKG2D and DNAM-1 receptors

et al. 2015

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Formation of polyploid or aneuploid cells is a pathological hallmark of malignant tumors. Cell cycle checkpoint mechanisms play a crucial role in ensuring genomic integrity during mitosis, avoiding the generation of aneuploid cells. Additionally, cancer cell DNA ploidy is subjected to extrinsic controls operated by activation of adaptive immune responses mediated by T cells. NK cells exert a central role in the innate anticancer immunity; however, the mechanisms involved in the recognition of tumor cells by NK cells have not been fully elucidated. Herein, we report that drug-induced polyploidy in cancer cells activates antitumor responses mediated by NK cells. Thus, hyperploidy-inducing chemotherapeutic agents strongly upregulate the tumor expression of ligands for the NK cell activating receptors NKG2D and DNAM-1. Drug-induced hyperploidy modulated the repertoire of activating receptors and the cytokine profile of NK cells, rendering tumor cells more susceptible to NK cell-mediated lysis through the activation of NKG2D and DNAM-1 receptors. In addition, hyperploidization stimulated the production of IL-2 by CD4 T cells, which induced NK cell proliferation and activity. The stimulation of MICA, a key NKG2D ligand, in hyperploid cells was mainly mediated by ATM protein kinase. Likewise, pharmacological inhibition of key regulators of endoplasmic reticulum stress in certain cell models supports a role for this pathway in NKG2D ligand upregulation. Overall, our findings indicate that, besides the cytotoxic effect on tumor cells, the therapeutic activity of anti-mitotic drugs may be mediated by the induction of a coordinated antitumor immune response involving NK and T cells.

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Section: Introductionmentioning

confidence: 99%

Drug-induced hyperploidy stimulates an antitumor NK cell response mediated by NKG2D and DNAM-1 receptors

et al. 2015

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“…22,33 Cytokines such as IL-4 and TGF-β derived from the tumor microenvironment can down-regulate NKG2D expression on NK and CD8 + T cells and thereby dampen anti-tumor activit. 34–36 In contrast, cytokines that function through common γ chain receptors, including IL-2, IL-7, and IL-15, can support NKG2D expression on immune cell.…”

Section: Discussionmentioning

confidence: 99%

“…34–36 In contrast, cytokines that function through common γ chain receptors, including IL-2, IL-7, and IL-15, can support NKG2D expression on immune cell. 33 These findings prompted us to ascertain the importance of activating DAP10 signaling in T cells to facilitate tumor eradication. We incorporated the DAP10 cytoplasmic domain into second-generation CAR vectors, and found the enhanced cytotoxcity and cytokine secretion by these CAR transduced human T cells.…”

Section: Discussionmentioning

confidence: 99%

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

et al. 2018

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Chimeric antigen receptor (CAR) T cell immunotherapies have shown remarkable efficacy in treating multiple types of hematological malignancies but are not sufficiently effective at treating solid tumors. NKG2D is a strong activating receptor for NK cells and a co-stimulatory receptor for T cells. NKG2D signal transduction depends on DNAX-activating protein 10 (DAP10). Here, we introduced the cytoplasmic domain of DAP10 into the second-generation CARs M28z and G28z to generate M28z10 and G28z10, which target mesothelin (MSLN) and glypican 3 (GPC3), respectively. T cells expressing M28z10 or G28z10 showed enhanced and prolonged effector function against MSLN+ lung cancer or GPC3+ hepatocellular carcinoma cell lines in culture and secreted elevated levels of cytokines, including IL-2, IFN-γ, granzyme B, and GM-CSF. In addition, M28z10 CAR-T cells showed greater anti-tumor activity than those expressing M28z in both A549 cell line xenografts and human lung cancer patient-derived xenografts (PDX). Similarly, G28z10 exhibited higher efficacy in causing tumor regression than did G28z in hepatocellular carcinoma PDX. Therefore, our results show that DAP10 signaling contributes to the function of CAR-T cells in both lung cancer and hepatocellular carcinoma and can enhance the efficacy of CAR-T cells.

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“…MICA is expressed on tumors or stressed cells and is a ligand for the activating receptor NKG2D. This receptor, which recognizes both human and murine tumor cells, plays an important role in the immune control of cancers [22].…”

Section: Discussionmentioning

confidence: 99%

Atorvastatin-Induced Inhibition of Human Melanoma In Vivo Development

Teiti¹,

Sarrabayrouse²

2016

Immunother Open Acc

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Statins, 3-hydroxy 3-methylglutaryl CoA (HMG-CoA) reductase inhibitors, are pleiotropic pharmacological inhibitors, which block the mevalonate synthesis pathway. They are widely used as hypocholesterolemic agents and have shown protective effects against cancers.Our previous data showed that statin treatment induced MHC class I chain-related protein A (MICA) membrane overexpression in human melanoma cells, which increased their sensitivity to NK cell cytotoxicity and thus the inhibition of tumor development. MICA is a ligand of the NK cell activating receptor NKG2D. This receptor is essential for NK cell control of tumor development and it has the unique property of being able to recognize tumor cells of both murine and human origin.Here, using atorvastatin and the WM-266-4 melanoma cell line, we first confirmed that statin treatment enhances MICA membrane expression and decreases local tumor growth and pulmonary metastasis implantation in vivo. Furthermore our new experiments showed that atorvastatin intraperitoneal repeated injections induced a reduction of tumor growth following subcutaneous implantation of untreated WM 266-4 cells into NMRI nude mice and favored the innate anti-melanoma immune response by increasing splenic NK cell concentration and activation. This report confirms that statins could become effective pharmacological agents for melanoma immunotherapy.

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NKG2D signaling in cancer immunosurveillance

Cited by 112 publications

References 154 publications

Drug-induced hyperploidy stimulates an antitumor NK cell response mediated by NKG2D and DNAM-1 receptors

Drug-induced hyperploidy stimulates an antitumor NK cell response mediated by NKG2D and DNAM-1 receptors

DNAX-activating protein 10 co-stimulation enhances the anti-tumor efficacy of chimeric antigen receptor T cells

Atorvastatin-Induced Inhibition of Human Melanoma In Vivo Development

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