Mutations in the IFNγ-JAK-STAT pathway causing resistance to immune checkpoint inhibitors in melanoma increase sensitivity to oncolytic virus treatment.

Abstract

Purpose: Next-generation sequencing studies and CRISPR-Cas9 screens have established mutations in the interferon (IFN)γ-JAK-STAT pathway as an ICI resistance mechanism in a subset of melanoma patients. We hypothesized ICI resistance mutations in the IFNγ pathway would simultaneously render melanomas susceptible to oncolytic virus (OV) therapy. Experimental design: Cytotoxicity experiments were performed with a number of OVs on a matched melanoma cell line pair generated from a baseline biopsy and a progressing lesion with complete JAK2 loss from a patient that relapsed on anti-PD-1 therapy, in melanoma lines following JAK1/2 RNAi and pharmacological inhibition and in Jak2 KO B16-F10 mouse melanomas. Furthermore, we estimated the frequency of genetic alterations in the IFNγ-JAK-STAT pathway in human melanomas. Results: The melanoma line from an anti-PD-1 progressing lesion was 7- and 22-fold more sensitive to the modified OVs, vesicular stomatitis virus (VSV-Δ51) and herpes simplex virus 1 (HSV1-dICP0), respectively, compared to the line from the baseline biopsy. RNAi, JAK1/2 inhibitor studies, and in vivo studies of Jak2 KOs B16-F10 melanomas revealed a significant increase in VSV-Δ51 sensitivity with JAK/STAT pathway inhibition. Our analysis of TCGA data estimated that ~11% of ICI-naïve cutaneous melanomas have alterations in IFNγ pathway genes that may confer OV susceptibility. Conclusion: We provide mechanistic support for the use of OVs as a precision-medicine strategy for both salvage therapy in ICI-resistant and first-line treatment in melanomas with IFNγ-JAK-STAT pathway mutations. Our study also supports JAK inhibitor-OV combination therapy for treatment-naive melanomas without IFN signaling defects.