Abstract A77: Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual costimulation of CD8 T cells and enables sMIC+ tumors to respond to PD1/PD-L1 blockade therapy

Abstract

Abstract Background: Insufficient costimulation accounts for a great deal of the suboptimal activation of cytotoxic CD8 T cells (CTLs) and presumably unsatisfactory clinical expectation of PD1/PDL1 therapy. Tumor-derived soluble NKG2D ligands are associated with poor clinical response to PD1/PDL1 blockade therapy in cancer patients. One of the most frequently occurring tumor-derived soluble NKG2D ligands, the soluble MHC I chain-related molecule (sMIC), can impair costimulation to CD8 T cells. We investigated whether cotargeting sMIC can provide optimal costimulation to CTLs and enhance the therapeutic effect of PD1/PDL1 blockades. Methods: Single-agent therapy of a PD1/PDL1 blockade antibody or a sMIC-targeting non-blocking antibody or a combination therapy of the two antibodies were applied to well-characterized preclinical MIC/sMIC+ tumor models that closely resemble the NKG2D-mediated oncoimmune dynamics of MIC+ cancer patients. Therapeutic efficacy and associated effector mechanisms were evaluated. Results: We show that antibody cotargeting sMIC enables or enhances the response of sMIC+ tumors to PD1/PD-L1 blockade therapy. The therapy response of the combination therapy was associated with enhanced antigen-specific CD8 T-cell enrichment and function in tumors. We show that cotargeting sMIC with a nonblocking antibody provides antigen-specific CD8 T cells with NKG2D and CD28 dual costimulation, in addition to elimination of inhibitory signals, and thus amplifies antigen-specific CD8 T-cell antitumor responses. Conclusion: Our findings provide the proof-of-concept rationale and previously undiscovered mechanisms for cotargeting sMIC to enable and enhance the response to PD1/PDL1 blockade therapy in sMIC+ cancer patients. Citation Format: Jinyu Zhang, Pablo Larrocha, Payal Dhar, Jennifer Wu. Antibody targeting tumor-derived soluble NKG2D ligand sMIC provides dual costimulation of CD8 T cells and enables sMIC+ tumors to respond to PD1/PD-L1 blockade therapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr A77.