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Journal of Hematology & Oncology

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01-12-2020 | Melanoma | Research

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

Authors: Fahmin Basher, Payal Dhar, Xin Wang, Derek A. Wainwright, Bin Zhang, Jeffrey Sosman, Zhe Ji, Jennifer D. Wu

Published in: Journal of Hematology & Oncology | Issue 1/2020

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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Title: Antibody targeting tumor-derived soluble NKG2D ligand sMIC reprograms NK cell homeostatic survival and function and enhances melanoma response to PDL1 blockade therapy
Authors: Fahmin Basher
Payal Dhar
Xin Wang
Derek A. Wainwright
Bin Zhang
Jeffrey Sosman
Zhe Ji
Jennifer D. Wu
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Melanoma
Melanoma
Published in: Journal of Hematology & Oncology / Issue 1/2020
Electronic ISSN: 1756-8722
DOI: https://doi.org/10.1186/s13045-020-00896-0

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Abstract

Background

Methods

Results

Conclusions

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