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      Antibody targeting tumor-derived soluble NKG2D ligand sMIC reprograms NK cell homeostatic survival and function and enhances melanoma response to PDL1 blockade therapy

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          Abstract

          Background

          Melanoma patients who have detectable serum soluble NKG2D ligands either at the baseline or post-treatment of PD1/PDL1 blockade exhibit poor overall survival. Among families of soluble human NKG2D ligands, the soluble human MHC I chain-related molecule (sMIC) was found to be elevated in melanoma patients and mostly associated with poor response to PD1/PDL1 blockade therapy.

          Methods

          In this study, we aim to investigate whether co-targeting tumor-released sMIC enhances the therapeutic outcome of PD1/PDL1 blockade therapy for melanoma. We implanted sMIC-expressing B16F10 melanoma tumors into syngeneic host and evaluated therapeutic efficacy of anti-sMIC antibody and anti-PDL1 antibody combination therapy in comparison with monotherapy. We analyzed associated effector mechanism. We also assessed sMIC/MIC prevalence in metastatic human melanoma tumors.

          Results

          We found that the combination therapy of the anti-PDL1 antibody with an antibody targeting sMIC significantly improved animal survival as compared to monotherapies and that the effect of combination therapy depends significantly on NK cells. We show that combination therapy significantly increased IL-2Rα (CD25) on NK cells which sensitizes NK cells to low dose IL-2 for survival. We demonstrate that sMIC negatively reprograms gene expression related to NK cell homeostatic survival and proliferation and that antibody clearing sMIC reverses the effect of sMIC and reprograms NK cell for survival. We further show that sMIC/MIC is abundantly present in metastatic human melanoma tumors.

          Conclusions

          Our findings provide a pre-clinical proof-of-concept and a new mechanistic understanding to underscore the significance of antibody targeting sMIC to improve therapeutic efficacy of anti-PD1/PDL1 antibody for MIC/sMIC + metastatic melanoma patients.

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          Most cited references 34

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          Roles of the NKG2D immunoreceptor and its ligands.

          According to present concepts, innate immunity is regulated by receptors that determine danger levels by responding to molecules that are associated with infection or cellular distress. NKG2D is, perhaps, the best characterized receptor that is associated with responses to cellular distress, defined as transformation, infection or cell stress. This review summarizes recent findings that concern NKG2D, its ligands, its signalling properties and its role in disease, and provides a framework for considering how the induction of immune responses can be regulated by cellular responses to injury.
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            Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma.

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              Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell–driven tumor immunity

              MICA and MICB are expressed by many human cancers as a result of cellular stress, and can tag cells for elimination by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA α 3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells. These antibodies inhibited tumor growth in multiple fully immunocompetent mouse models and reduced human melanoma metastases in a humanized mouse model. Antitumor immunity was mediated mainly by natural killer (NK) cells through activation of NKG2D and CD16 Fc receptors. This approach prevents the loss of important immunostimulatory ligands by human cancers and reactivates antitumor immunity.
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                Author and article information

                Contributors
                jennifer.wu@northwestern.edu
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                9 June 2020
                9 June 2020
                2020
                : 13
                Affiliations
                [1 ]GRID grid.259828.c, ISNI 0000 0001 2189 3475, Department of Microbiology and Immunology, , Medical University of South Carolina, ; Charleston, SC 29425 USA
                [2 ]GRID grid.16753.36, ISNI 0000 0001 2299 3507, Department of Urology, Feinberg School of Medicine, , Northwestern University, ; Chicago, IL 60611 USA
                [3 ]GRID grid.16753.36, ISNI 0000 0001 2299 3507, Driskill Graduate Program in Life Science, Feinberg School of Medicine, , Northwestern University, ; Chicago, IL 60611 USA
                [4 ]GRID grid.16753.36, ISNI 0000 0001 2299 3507, Department of Pharmacology, Feinberg School of Medicine, , Northwestern University, ; Chicago, IL 60611 USA
                [5 ]GRID grid.16753.36, ISNI 0000 0001 2299 3507, Department of Neurological Surgery, Feinberg School of Medicine, , Northwestern University, ; Chicago, IL 60611 USA
                [6 ]GRID grid.16753.36, ISNI 0000 0001 2299 3507, Department of Microbiology and Immunology, Feinberg School of Medicine, , Northwestern University, ; Chicago, IL 60611 USA
                [7 ]GRID grid.16753.36, ISNI 0000 0001 2299 3507, Division of Hematology and Oncology, Feinberg School of Medicine, , Northwestern University, ; Chicago, IL 60611 USA
                [8 ]GRID grid.16753.36, ISNI 0000 0001 2299 3507, Department of Biomedical Engineering, McCormick School of Engineering, , Northwestern University, ; Evanston, IL 60628 USA
                [9 ]GRID grid.26790.3a, ISNI 0000 0004 1936 8606, Current address: Department of Medicine, Miller School of Medicine, , University of Miami, ; Miami, FL USA
                Article
                896
                10.1186/s13045-020-00896-0
                7285527
                32517713
                © The Author(s) 2020

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: 1R01CA208246
                Award ID: 1R01CA204021
                Categories
                Research
                Custom metadata
                © The Author(s) 2020

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