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      NKG2D and MICA/B shedding: a ‘tag game’ between NK cells and malignant cells


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          Natural killer (NK) cells are innate lymphocytes with cytotoxic functions and recognise target cells with the NK group 2D (NKG2D) receptor. Tumor cells are marked for NK‐cell‐mediated destruction upon expression of MICA and MICB (MICA/B), which are NKG2D ligands upregulated by many human cancers in response to cellular stress pathways associated with malignant transformation such as DNA damage and accumulation of misfolded proteins. However, MICA/B proteins are downregulated by tumor cells via intriguing molecular mechanisms, such as post‐translational modifications in which the external domains of MICA/B are proteolytically cleaved by surface proteases and shed into the extracellular space. MICA/B shedding by cancer cells causes effective escape from NKG2D recognition and allows the development of cancers. Patients frequently have increased concentrations of soluble MICA/B molecules shed in the blood plasmas and sera, thus indicating that MICA/B shedding is a therapeutic target in immune‐oncology. Here, we review the clinical significance of MICA/B shedding in cancer as well as novel immunotherapeutic approaches that aim to restore NKG2D‐mediated surveillance. We also briefly discuss potential roles of MICA/B shedding beyond oncology, such as in viral infections and immune tolerance. This review will help to inform the future developments of NKG2D‐based immunotherapies.


          The NKG2D‐MICA/B axis is a major mechanism of immunosurveillance for abnormal cells, but MICA/B are downregulated via proteolytic cleavage to enable escape by many human cancers. MICA/B shedding is a new therapeutic target, and multiple immunotherapeutic strategies are underdevelopment and hold promise for cancer treatment. This review highlights key approaches that aim to restore this mechanism of surveillance for cancers.

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          Most cited references61

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          Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma.

          Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown.
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            Is Open Access

            NK Cells Stimulate Recruitment of cDC1 into the Tumor Microenvironment Promoting Cancer Immune Control

            Summary Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are associated with increased overall patient survival. Notably, tumor production of prostaglandin E2 (PGE2) leads to evasion of the NK cell-cDC1 axis in part by impairing NK cell viability and chemokine production, as well as by causing downregulation of chemokine receptor expression in cDC1. Our findings reveal a cellular and molecular checkpoint for intratumoral cDC1 recruitment that is targeted by tumor-derived PGE2 for immune evasion and that could be exploited for cancer therapy.
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              Activation of NK cells and T cells by NKG2D, a receptor for stress-inducible MICA.

              Stress-inducible MICA, a distant homolog of major histocompatibility complex (MHC) class I, functions as an antigen for gammadelta T cells and is frequently expressed in epithelial tumors. A receptor for MICA was detected on most gammadelta T cells, CD8+ alphabeta T cells, and natural killer (NK) cells and was identified as NKG2D. Effector cells from all these subsets could be stimulated by ligation of NKG2D. Engagement of NKG2D activated cytolytic responses of gammadelta T cells and NK cells against transfectants and epithelial tumor cells expressing MICA. These results define an activating immunoreceptor-MHC ligand interaction that may promote antitumor NK and T cell responses.

                Author and article information

                Clin Transl Immunology
                Clin Transl Immunology
                Clinical & Translational Immunology
                John Wiley and Sons Inc. (Hoboken )
                22 December 2020
                : 9
                : 12 ( doiID: 10.1002/cti2.v9.12 )
                : e1230
                [ 1 ] Precision Immunology Institute New York NY USA
                [ 2 ] Department of Oncological Sciences New York NY USA
                [ 3 ] The Tisch Cancer Institute of the Icahn School of Medicine at Mount Sinai New York NY USA
                Author notes
                [*] [* ] Correspondence

                L Ferrari de Andrade, Precision Immunology Institute, New York, NY, USA.

                E‐mail: Lucas.FerrarideAndrade@ 123456mssm.edu

                Author information
                © 2020 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

                : 28 October 2020
                : 02 December 2020
                : 05 December 2020
                Page count
                Figures: 2, Tables: 1, Pages: 11, Words: 6847
                Funded by: Opportunities Fund at CUNY Macaulay Honors College, USA
                Funded by: Jennifer J Raab Fellowship at CUNY Hunter College, USA
                Special Feature Review
                Special Feature Review
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                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:22.12.2020

                cancer immunotherapy,mica and micb,nk cells,nkg2d,proteolytic shedding


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