MYC Induces Immunotherapy and IFNγ Resistance Through Downregulation of JAK2

Immunotherapy has revolutionized the treatment of advanced melanoma. Because the pathways mediating resistance to immu-notherapy are largely unknown, we conducted transcriptome profiling of preimmunotherapy tumor biopsies from patients with melanoma that received PD-1 blockade or adoptive cell therapy with tumor-infiltrating lymphocytes. We identified two melanoma-intrinsic, mutually exclusive gene programs, which were controlled by IFNy and MYC, and the association with immunotherapy outcome. MYC-overexpressing melanoma cells exhibited lower IFNy responsiveness, which was linked with JAK2 downregulation. Luciferase activity assays, under the con-trol of JAK2 promoter, demonstrated reduced activity in MYC-overexpressing cells, which was partly reversible upon mutagen-esis of a MYC E-box binding site in the JAK2 promoter. Moreover, silencing of MYC or its cofactor MAX with siRNA increased JAK2 expression and IFNy responsiveness of melano-mas, while concomitantly enhancing the effector functions of T cells coincubated with MYC-overexpressing cells. Thus, we pro-pose that MYC plays a pivotal role in immunotherapy resistance through downregulation of JAK2.