Melanocyte PDL1 promotes early tumor progression in a novel autochthonous NRAS-mutant melanoma model
نویسندگان
چکیده
Abstract Tumor-intrinsic PDL1 drives melanoma treatment resistance. Melanocytes (melanoma cell-of-origin) do not express PDL1, but is expressed in malignant melanomas, suggesting melanocyte promotes melanomagenesis. We developed a novel autochthonous mouse model that develops NRAS Q61R-mutant melanomas lacking only melanocytes (PDL1 KOTN Q61R) and littermate controls +/+TN Q61R). induced mice with 4-OH tamoxifen ± UV exposure to accelerate development. Tumor latency significantly increased KOvs. Q61Rmice at 0 kJ/m 2and 2 2UV(p<0.02), melanocyte/tumor Latencies were similar 4.5 2, immune contributions, e.g., from local immunosuppression. derived transplantable cell lines tumors. Q61Rcell had mTORC1 stemness, reduced STING Chk1 inhibitor sensitivity vitro vivo vs. Q61R, phenocopied by KOB16. suppressed ERK signals (NRAS target) TN Q61Rvs. KOcell promoted resistance NRAS-targeting small molecule drugs, tumor signals. Transplanted 2UV-inducedPDL1 Q61Rtumors resistant αPD1, αPDL1, αPDL2, CD122-biased IL2 WT B16 which are sensitive biased IL2. Our allows studies of melanomagenesis progression distinguishes bona fide cell-intrinsic This research was funded the NIH T32GM113896 (STX MSTP) Award (C.O.) NCI (CA204965, CA054515) supported Curiel.
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ژورنال
عنوان ژورنال: Journal of Immunology
سال: 2023
ISSN: ['1550-6606', '0022-1767']
DOI: https://doi.org/10.4049/jimmunol.210.supp.88.11