SOX10 Regulates Melanoma Immunogenicity through an IRF4–IRF1 Axis

Abstract

the efficacy of combination therapy with an anti-PD-1 antibody and histone deacetylase inhibitor against a clinically relevant melanoma model. Thus, the SOX10–IRF4–IRF1 axis serves as a potential target that can bypass JAK-STAT signaling to immunologically warm up melanoma with a "cold" tumor immune microenvironment. Loss-of-function mutations of JAK1/2 impair cancer cell responsiveness to IFNg and immunogenicity. Therefore, an understanding of compensatory pathways to activate IFNg signaling in cancer cells is clinically important for the success of immunotherapy. Here we demonstrate that the transcription factor SOX10 hinders immunogenicity of melanoma cells through the IRF4–IRF1 axis. Genetic and pharmacologic approaches revealed that SOX10 repressed IRF1 transcription via direct induction of a negative regulator, IRF4. The SOX10–IRF4–IRF1 axis regulated PD-L1 expression independently of JAK–STAT pathway activity, and suppression of SOX10 increased