Abstract 2864: Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling

Abstract Therapeutic resistance to immune checkpoint blockers (ICBs) is a pressing issue, limiting ICB efficacy to a small proportion of cancer patients. Concerted efforts from our group and others have identified that loss of IFN-γ signaling genes in melanoma is a major mechanism of resistance to ICBs. However, strategies of overcoming this resistance have been largely elusive. Moreover, given the indispensable role of T cells in governing ICBs, little is known about how tumor-intrinsic loss of IFN-γ signaling impacts tumor-infiltrating T cells (TILs). In this study, we report that melanomas with defective IFN-γ signaling (IFNγR1KO) have reduced infiltration and function of TILs. Intriguingly, IFNγR1KO melanoma cells harbor a network of constitutively active protein tyrosine kinases (PTKs) centered on JAK1/2, essential downstream components of the IFN-γ signaling. Additional mechanistic studies reveal that JAK1/2 activation is mediated by augmentation of the mTOR pathway. Importantly, targeting active JAK1/2 with FDA-approved Ruxolitinib (Ruxo) selectively suppresses growth of IFNγR1KO but not scrambled control melanoma, in a T cell and host TNF-dependent manner. Together, our results highlight an important role of tumor-intrinsic IFN-γ signaling in shaping TILs and manifest a therapeutic target that can be leveraged to bypass ICB resistance of melanomas defective of IFN-γ signaling. Citation Format: Hongxing Shen, Fengyuan Huang, Xiangmin Zhang, Oluwagbemiga A. Ojo, Yuebin Li, Hoa Quang Trummell, Joshua C. Anderson, John Fiveash, Markus Bredel, Eddy Yang, Christopher Willey, Zechen Chong, James Bonner, Lewis Z. Shi. Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling [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 2864.