Sex-based mutational landscape confers sensitivity to checkpoint blockade immunotherapy in cutaneous melanoma

Abstract

Anti-programmed cell death protein 1 (PD-1) therapy provided superior benefits in skin cutaneous melanoma (SKCM), but only a minority of patients responded. As SKCM had sex-based immunological differences, we sought to explore the potential interactions between sex and clinical responses to anti-PD-1 therapy in SKCM. We found that sex had significant effects on anti-PD-1 therapy. Tumor mutation burden (TMB) and neoantigen burden significantly correlated with the clinical responses to anti-PD-1 therapy only in males. Meanwhile, we recruited The Cancer Genome Atlas (TCGA) database to explore sex-based differences of the tumor microenvironment (TME) in SKCM. We observed that males with high TMB, especially in conjunction with interferon-gamma (IFN-γ) signaling, significantly correlated with increased PD-L1 expression, major histocompatibility complex (MHC) class I gene expression, and the infiltration of cytotoxic T lymphocytes (CTLs). In addition, TMB and anti-PD-1 efficacy in SKCM each correlated with homologous recombination repair (HRR) gene BRCA2 mutations, but only in males. Taken together, these data revealed that in SKCM, high TMB correlated with prominent immunotherapeutic TME only in males, and that gender should be taken into account when predicting the efficacy of anti-PD-1 therapy for SKCM.