Abstract 5963: Germline variant positive melanoma patients exhibit an enhanced inflammatory microenvironment

Abstract Germline pathogenic variants (gPV) in cancer susceptibility genes are present in roughly 15% of all melanoma diagnoses. Prior studies note improvements in checkpoint immunotherapy responsiveness in patients with a gPV, which is associated with an increased neo-antigen load in gPV patients. We have also previously reported improvements in melanoma specific survival (MSS) in gPV patients vs non-gPV. No studies to date have examined the immune environment in gPV patients which may account for improvements in survival. In our study, melanoma patients with a personal or family history of multiple cancers were offered germline testing utilizing a commercial germline cancer sequencing panel. Enrolled patients also received a blood draw with subsequent flow cytometry to analyze the immune phenotype. In a cohort of 540 melanoma patients, 80 had a gPV. Multivariable linear regression indicated that significantly fewer polymorphonuclear myeloid derived suppressor cells (PMN-MDSC’s) were noted relative to non-gPV patients when adjusting for melanoma stage at germline testing [β = -.45, 95% CI (-.76, -.15), p = .0036]. This difference was most significant in cutaneous, later stage (IIB-IV) patients, primarily stage III. We also interrogated patterns in gene signature between gPV and non-gPV patients in the TCGA PanCancer cutaneous melanoma cohort. We identified reductions in CCL27 (p = .007) and CCL1 (p = .06), genes associated with MDSC recruitment, across all stages in gPV patients, as well as reductions in ARG1 (p= .05) and S100A7 (p = .08), genes associated with PMN-MDSC’s, in later stage gPV patients. Pathway differences were analyzed using gene set enrichment analysis (GSEA). Analysis of Hallmark gene sets identified significantly upregulated signatures in inflammatory response, TNF-α signaling, IFN-γ signaling, and IL-2 STAT5 signaling in late stage gPV patients. KEGG pathway analysis further identified NK cell mediated cytotoxicity and TCR signaling as significantly upregulated in late stage gPV patients. Notably, fatty acid metabolism pathways, which have been implicated in immunosuppression through MDSC suppressive function, were downregulated in gPV patients. These results suggest that gPV melanoma is associated with both a depletion of PMN-MDSC’s and an upregulation of inflammatory microenvironmental genes in later stages which may explain improved outcomes. Citation Format: Alan Shen, Roshan Lodha, Brandon Bungo, Michelle Arbesman, Nikhil Pramod, Jennifer Ko, Brian Gastman, C. Marcela Diaz, Timothy Chan, Joshua Arbesman, Pauline Funchain. Germline variant positive melanoma patients exhibit an enhanced inflammatory microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5963.