Abstract
BackgroundMelanoma 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.MethodsIn 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.ResultsWe 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.ConclusionsOur 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.
Highlights
Immunotherapy by blocking the axis of the immune checkpoint molecule programmed cell death protein (PD1) or its ligand PDL1 has presented remarkable survival benefit and became a frontline treatment for metastatic or unresectable melanoma [1, 2]
Our findings provide a pre-clinical proof-of-concept and a new mechanistic understanding to underscore the significance of antibody targeting soluble human MHC I chain-related molecule (sMIC) to improve therapeutic efficacy of anti-PD1/PDL1 antibody for MHC I chain-related molecule (MIC)/sMIC+ metastatic melanoma patients
We have previously described that clearance of tumorderived soluble NKG2D ligands, sMIC, with a monoclonal antibody B10G5 restores NK cell homeostatic renewal, enhances NK cell and antigen-specific CD8 T cell function, immobilizes NK and CD8 T cell to the tumors, and re-modulates tumor microenvironment by eliminating myeloid-derived suppressive cells (MDSCs) and tumor-associated macrophages [17, 18]
Summary
Immunotherapy by blocking the axis of the immune checkpoint molecule programmed cell death protein (PD1) or its ligand PDL1 has presented remarkable survival benefit and became a frontline treatment for metastatic or unresectable melanoma [1, 2]. Soluble human NKG2D ligands have been shown to subvert antitumor immunity through multiple mechanisms, including but not limited to, perturbing NK cell homeostatic maintenance and function, impairing CD8 T cell function by destabilizing CD3ζ [16], and expanding myeloid-derived suppressive cells (MDSCs) in the tumor microenvironment [17]. These mechanistic understandings along with the reported clinical observations prompt us to test the hypothesis that co-targeting tumor-derived soluble NKG2D ligands would enhance melanoma tumor response to PD/PDL1 blockade therapy. 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
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