Adipocyte PDL1 depletion sensitizes NRASQ61R-mutant melanoma to anti-PDL1 immune checkpoint blockade (ICB) 3414

Abstract Description Adipocytes are a key component of the tumor microenvironment, but their contributions to ICB response remain relatively understudied. We have previously reported that adipocyte PDL1KO (adipo-PDL1KO) boosts CD8+ T cell function and improves αPDL1 efficacy in adipocyte-rich E0771 breast cancer and B16 melanoma. Our lab has developed a novel NRASQ61R-mutant, PDL1+ transplantable melanoma model (NCH1) that has an adipocyte-rich tumor microenvironment. We challenged wild-type (WT) and adipo-PDL1KO mice with NCH1 orthotopically and found that while αPDL1 treated NCH1 tumors in WT mice (p = 0.011), αPDL1 response in adipo-PDL1KO mice was significantly improved (p < 0.0001). In a complementary approach, we pharmacologically inhibited adipo-PDL1 expression with the validated PPARγ inhibitor GW9662, as PDL1+ adipocytes differentiate from PDL1- adipocytes through PPARγ. GW9662+αPDL1 phenocopied adipo-PDL1KO in controlling NCH1 growth (p < 0.0001 vs single agents). We did not observe significant chances in tumor-infiltrating immune cell prevalence or function with flow cytometry, suggesting that GW9662 may improve αPDL1 through enhancing immune cell colocalization or other mechanisms. For rapid clinical translation, we tested imatinib, an orally bioavailable FDA-approved drug that inhibits PPARγ, but it failed to improve ICB response in E0771 and 4T1 breast cancer models. These results support developing clinical strategies to target adipo-PDL1 to improve treatment responses. Funding Sources Supported by: NCI (CA252057, CA268641, CA246707, CA292467, CA279566), 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)