Melanocyte PDL1 promotes early tumor progression in a novel autochthonous NRAS-mutant melanoma model

Abstract

Abstract Tumor-intrinsic PDL1 drives melanoma treatment resistance. Melanocytes (melanoma cell-of-origin) do not express PDL1, but PDL1 is expressed in malignant melanomas, suggesting melanocyte PDL1 promotes melanomagenesis. We developed a novel autochthonous mouse model that develops NRAS Q61R-mutant melanomas lacking PDL1 only in melanocytes (PDL1 KOTN Q61R) and littermate controls (PDL1 +/+TN Q61R). We induced mice with 4-OH tamoxifen ± UV exposure to accelerate melanoma development. Tumor latency significantly increased in PDL1 KOvs. PDL1 +/+TN Q61Rmice at 0 kJ/m 2and 2 kJ/m 2UV(p<0.02), suggesting melanocyte/tumor PDL1 promotes melanomagenesis. Latencies were similar at 4.5 kJ/m 2, suggesting immune contributions, e.g., from local immunosuppression. We derived transplantable cell lines from autochthonous tumors. PDL1 +/+TN Q61Rcell lines had increased mTORC1 and stemness, and reduced STING and reduced Chk1 inhibitor sensitivity in vitro and in vivo vs. PDL1 KOTN Q61R, phenocopied by PDL1 KOB16. Tumor PDL1 suppressed ERK signals (NRAS target) in TN Q61Rvs. PDL1 KOcell lines and promoted resistance to NRAS-targeting small molecule drugs, suggesting tumor PDL1 promotes NRAS signals. Transplanted 4.5 kJ/m 2UV-inducedPDL1 KOTN Q61Rtumors were resistant to αPD1, αPDL1, αPDL2, and CD122-biased IL2 in WT mice vs. B16 melanomas, which are sensitive to biased IL2. Our model allows studies of PDL1 signals in melanomagenesis and progression and distinguishes bona fide cell-intrinsic PDL1 signals. This research was funded by the NIH T32GM113896 (STX MSTP) Award (C.O.) and the NCI (CA204965, CA054515) supported Curiel.