Combined blockade of B7-H3 and CD47 immune checkpoints is a new therapeutic strategy for ß-catenin driven melanomas [single cell CD45+ YUMM 2.1]

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 it's co-targeting with CD47 as a novel combination of immune checkpoint inhibitors in melanoma that calls for testing in clinical trials. Overall design: To identify the composition of the immune cell infiltrate within the tumor milieu, we analyzed the major immune cell subsets and functional categories (i.e. CD4+ T cells, CD8+ T cells, NK cells, dendritic cells, B cells, and macrophages) from the dissected tumors in mice treated with isotype control, anti-B7-H3 antibody, anti-PD1, and the combination of both antibodies using CD45+ sorted RNA-sequencing experiments. Each sample (GSM) is multiplexed and can be demultiplexed using the information in the HTO sample. Each replicate is represented by two processed data archives appended with either '_1' or '_2'. The sequencing library was run in two separate lanes to reach a higher number of cells and reads sequenced. Each lane of data was used to produce one archive of processed data per replicate.