B7‐H3 drives immunosuppression and Co‐targeting with CD47 is a new therapeutic strategy in β‐catenin activated melanomas

Abstract

AbstractIn melanoma, immune cell infiltration into the tumor is associated with better patient outcomes and response to immunotherapy. T‐cell non‐inflamed tumors (cold tumors) are associated with tumor cell‐intrinsic Wnt/β‐catenin activation, and are typically resistant to anti‐PD‐1 alone or in combination with anti‐CTLA‐4 therapy. Reversal of the ‘cold tumor’ phenotype and identifying new effective immunotherapies are challenges. We sought to investigate the role of a newer immunotherapy agent, B7‐H3, in this setting. RNA sequencing was used to identify co‐targeting strategies upon B7‐H3 inhibition in a well‐defined preclinical melanoma model driven by β‐catenin. We found that immune checkpoint molecule B7‐H3 confers a suppressive tumor microenvironment by modulating antiviral signals and innate immunity. B7‐H3 inhibition led to an inflamed microenvironment, up‐regulation of CD47/SIRPa signaling, and together with blockade of the macrophage checkpoint CD47 resulted in additive antitumor responses. We found that the antitumor effects of the B7‐H3/CD47 antibody combination were dependent on cytokine signaling pathways (CCR5/CCL5 and IL4).