Melanocyte PDL1 promotes early tumor progression in a novel autochthonous NRAS-mutant melanoma model
Year: 2023
Type: conference-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 NRASQ61R-mutant melanomas lacking PDL1 only in melanocytes (PDL1KOTNQ61R) and littermate controls (PDL1+/+ TNQ61R). We induced mice with 4-OH tamoxifen ± UV exposure to accelerate melanoma development. Tumor latency significantly increased in PDL1KO vs. PDL1+/+ TNQ61R mice at 0 kJ/m2 and 2 kJ/m2UV(p<0.02), suggesting melanocyte/tumor PDL1 promotes melanomagenesis. Latencies were similar at 4.5 kJ/m2, suggesting immune contributions, e.g., from local immunosuppression. We derived transplantable cell lines from autochthonous tumors. PDL1+/+ TNQ61R cell lines had increased mTORC1 and stemness, and reduced STING and reduced Chk1 inhibitor sensitivity in vitro and in vivo vs. PDL1KOTNQ61R, phenocopied by PDL1KO B16. Tumor PDL1 suppressed ERK signals (NRAS target) in TNQ61R vs. PDL1KO cell lines and promoted resistance to NRAS-targeting small molecule drugs, suggesting tumor PDL1 promotes NRAS signals. Transplanted 4.5 kJ/m2UV-inducedPDL1KO TNQ61R tumors 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.
Source: The Journal of Immunology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4385687939