Overcoming immunotherapy resistance in melanoma defective of IFN-γ signaling

Abstract

Abstract Therapeutic resistance to immune checkpoint blockers (ICBs) in melanoma patients is a pressing issue. Initial efforts from others and us show that ICB resistance can derive from melanoma-intrinsic loss of the IFN-γ signaling, which occurs in ~20.9% of the 287 melanoma cases (CBioPortal), based on the cumulative frequency of damaging mutations of 12 core genes. However, how to overcome this resistance mechanism remains largely unexplored. Moreover, given the indispensable role of tumor-infiltrating T cells (TILs) in ICBs, little is known about how tumor-intrinsic loss of IFN-γ signaling (IFNγR1 KO) impacts TILs. Here, we report that IFNγR1 KOmelanomas have reduced infiltration and function of TILs. Combining kinomics, RNA-seq, and proteomics, we unveil that Janus Kinase 1 and 2 (JAK1-2), key downstream kinases in the IFN-γ signaling cascade, are constitutively active, mediated by heightened mTOR. Importantly, mTOR inhibition with Everolimus induces a potent suppression of IFNγR1 KOmelanoma growth, particularly when combined with ICBs, despite its reported modest effects on WT tumors; similarly, targeting JAK1-2 with Ruxolitinib (Ruxo) selectively impedes the growth of IFNγR1 KObut not WT melanomas, revealing effective “targeted” treatments for ICB resistance. Mechanistically, these therapeutics successfully reprogram “cold” TILs in IFNγR1 KOmelanoma to functional effectors (e.g., increased production of TNF), and deleting T cells or using TNF KOmice completely abrogates Ruxo efficacy. Altogether, our results highlight an active role of tumor-intrinsic IFN-γ signaling in shaping TILs and manifest therapeutic targets that can be harnessed to bypass ICB resistance of melanomas defective of IFN-γ signaling. Supported by grants from NIH (1R21CA259721-01A1) and from DoD Idea Award (ME210108)