Mutations in the IFNγ-JAK-STAT Pathway Causing Resistance to Immune Checkpoint Inhibitors in Melanoma Increase Sensitivity to Oncolytic Virus Treatment
| Autor: | Mozhdeh Ahanfeshar-Adams, Dirk Schadendorf, Tan-Trieu Nguyen, LeeAnn Ramsay, Mathieu Lajoie, Ian R. Watson, Tommy Alain |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Combination therapy Medizin Melanoma Experimental Salvage therapy medicine.disease_cause Mice 03 medical and health sciences 0302 clinical medicine RNA interference Cell Line Tumor medicine Animals Humans Immune Checkpoint Inhibitors Janus Kinases biology business.industry Melanoma JAK-STAT signaling pathway medicine.disease biology.organism_classification Oncolytic virus Oncolytic Viruses STAT Transcription Factors 030104 developmental biology Herpes simplex virus Oncology Vesicular stomatitis virus 030220 oncology & carcinogenesis Mutation Cancer research business Signal Transduction |
| Zdroj: | Clinical Cancer Research. 27:3432-3442 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-20-3365 |
| Popis: | Purpose: Next-generation sequencing studies and CRISPR-Cas9 screens have established mutations in the IFNγ-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 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 RNA interference (RNAi) and pharmacologic inhibition and in Jak2 knockout (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, herpes simplex virus 1 (HSV1-dICP0) and vesicular stomatitis virus (VSV-Δ51), 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-Δ51 sensitivity with JAK/STAT pathway inhibition. Our analysis of The Cancer Genome Atlas data estimated that approximately 11% of ICI-naïve cutaneous melanomas have alterations in IFNγ 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 IFNγ-JAK-STAT pathway mutations. Our study also supports JAK inhibitor–OV combination therapy for treatment-naïve melanomas without IFN signaling defects. See related commentary by Kaufman, p. 3278 |
| Databáze: | OpenAIRE |
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