Mutations in the IFNγ-JAK-STAT Pathway Causing Resistance to Immune Checkpoint Inhibitors in Melanoma Increase Sensitivity to Oncolytic Virus Treatment

Purpose Next-generation sequencing studies and CRISPR-Cas9 screens have established mutations in the IFN gamma-JAK-STAT pathway as an immune checkpoint inhibitor (ICI) resistance mechanism in a subset of patients with melanoma. We hypothesized ICI resistance mutations in the IFN gamma 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 tha t relapsed on anti-PD-1 therapy, in melanoma lines following JAK1/2 RNA interference (RNAi) and pharmacologic inhibition and in Jak2knockout (KO) B16-F10 mouse melanomas. Furthermore, we estimated the frequency of genetic alterations in the IFN gamma-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, herpes simplex virus 1 (HSV1-dICP0) and vesicular stomatitis virus (VSV-Delta 51), respectively, compared with 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-Delta 51 sensitivity with JAK/STAT pathway inhibition. Our analysis of The Cancer Genome Atlas data estimated that approximately 11% of ICI-naive cutaneous melanomas have alterations in IFN gamma pathway genes that may confer OV susceptibility. Conclusions: 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 IFN gamma-JAK-STAT pathway mutations. Our study also supports JAK inhibitor-OV combination therapy for treatment-naive melanomas without IFN signaling defects.

Automated summary

Mutations in the IFN gamma-JAK-STAT pathway have been identified as a resistance mechanism to immune checkpoint inhibitors in a subset of patients with melanoma. Research has shown that melanomas with these mutations may exhibit increased sensitivity to oncolytic virus therapy, providing a potential precision medicine strategy for both salvage therapy in ICI-resistant cases and first-line treatment in melanomas with IFN gamma signaling defects. This study also supports the use of JAK inhibitor-OV combination therapy for treatment-naive melanomas without IFN signaling defects.