Combined blockade of B7-H3 and CD47 immune checkpoints is a new therapeutic strategy for ß-catenin driven melanomas [transfection]

In 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/ß-catenin activation, and are 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 in melanoma. In a well-established preclinical melanoma model driven by ß-catenin, we found that immune checkpoint molecule B7-H3 confers a suppressive tumor microenvironment by modulating antiviral signals and matricellular proteins. Its inhibition primes the microenvironment, and together with blockade of the macrophage checkpoint CD47, but not with anti-PD-1, results in synergistic anti-tumor responses. This study brings B7-H3 to the forefront as inducing a suppressive microenvironment when overexpressed, and co-targeting with CD47 as a novel combination of immune checkpoint inhibitors in melanoma that calls for testing in clinical trials. Overall design: To gain insight into its functions and examine the downstream effectors of B7-H3, we selected two human metastatic melanomacell lines, Hs. 688(A)T and Hs. 839T, with the highest levels of B7-H3 expression. Cells were transfected with either scrambled or B7-H3 specific siRNAs in triplicates (total 12 samples), and transcriptomes were analyzed via RNA-sequencing.