MYC induces immunotherapy and interferon-γ resistance through downregulation of JAK2

Immunotherapy revolutionized the treatment of advanced melanoma. As the pathways mediating resistance to immunotherapy are largely unknown, we conducted transcriptome profiling of pre-immunotherapy tumor biopsies from melanoma patients that received PD-1 blockade (n=36) or adoptive cell therapy with tumor infiltrating lymphocytes (n=37). We identified two melanoma-intrinsic mutually exclusive gene programs, which are controlled by interferon-γ and MYC, and determine immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower interferon-γ responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays under the control of JAK2 promoter demonstrated reduced activity in MYC-overexpressing cells, which was reversible upon mutagenesis of MYC E-box binding sites in the JAK2 promoter. Moreover, silencing of MYC or its co-factor MAX with siRNA increased JAK2 expression and interferon-γ responsiveness of melanomas, while concomitantly enhancing the effector functions of T-cells co-incubated with MYC-overexpressing cells. Thus, we propose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2. RNA-seq from pre-treatment tumor biopsies of advanced melanoma patients treated with PD-1 blockade (n=36) or TIL ACT (n=37)