Melanoma cell-of-origin (melanocyte) PDL1 deletion delays melanomagenesis that is overcome by UVB-induced immunosuppression through IFN-I signaling 2676

Abstract Description Tumor PDL1 is a well-defined immune checkpoint on established tumors, yet its influence on early tumor development is undefined. We developed a 4-OH tamoxifen (HT)-inducible mouse model that develops UVB-accelerable NRASQ61R-mutant (associated with UVB) melanomas that express (CTRL) or never express (melPDL1KO) PDL1 only in melanocytes. melPDL1KO mice had significantly delayed tumor development after HT induction ± clinically relevant 2.0 kJ/m2 UVB. Thus melPDL1 modulates the early tumor microenvironment (TME) to promote melanoma. This delay in tumor latency was abolished with 4.5 kJ/m2 UVB. As UVB induces type I IFN (IFN-I), we hypothesized that loss of melPDL1KO-dependent latency extension was due to UVB-induced, melPDL1-modulated IFN-I signaling. In support, transplantable cell lines derived from melPDL1KO tumors consistently had high baseline IFN-I signaling and a tumor inflammatory memory signature. PDL1KO skin exhibited suppressed IFN-I. melPDL1-dependent UVB effects reduced TME IFNγ in CD8+ T and NK cells, perhaps from chronic IFN-I-mediated immunosuppression and/or tumor inflammatory memory. In support, IFNAR blockade at tumor induction restored melPDL1KO-dependent latency extension and significantly enhanced NK cell infiltration, suggesting NK cell IFN-I signaling is critical for melPDL1-driven melanomagenesis. Our studies define a novel role for PDL1 and IFN-I in tumorigenesis and suggest high IFN-I as a poor prognostic indicator in melanoma. Funding Sources NIH T32GM113896 (STX MSTP) Award (C.O. and C.M.) and the NCI F31CA281345 (C.O.). NCI (CA252057, CA268641, CA246707, CA292467), Gmelich chair and Guyre funds supported Curiel. Work was supported by the Dartmouth Cancer Center and DartLab, the Immune Monitoring and Flow Cytometry Shared Resource at the Dartmouth Cancer Center, with NCI Cancer Center Support Grant 5P30 CA023108-41. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)