دورية أكاديمية
أعرض في EDS

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

التفاصيل البيبلوغرافية
العنوان: Mutations in the IFNγ-JAK-STAT Pathway Causing Resistance to Immune Checkpoint Inhibitors in Melanoma Increase Sensitivity to Oncolytic Virus Treatment.
المؤلفون: Nguyen TT; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.; Department of Biochemistry, McGill University, Montréal, Québec, Canada., Ramsay L; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada., Ahanfeshar-Adams M; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada., Lajoie M; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada., Schadendorf D; Department of Dermatology, University Hospital Essen, University Duisburg-Essen, Essen, Germany.; German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Essen, Germany., Alain T; Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.; Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Canada., Watson IR; Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada. ian.watson2@mcgill.ca.; Department of Biochemistry, McGill University, Montréal, Québec, Canada.; Research Institute of the McGill University Health Centre, Montréal, Canada.
المصدر: Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2021 Jun 15; Vol. 27 (12), pp. 3432-3442. Date of Electronic Publication: 2021 Feb 16.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Denville, NJ : The Association, c1995-
مواضيع طبية MeSH: Melanoma, Experimental*/genetics , Melanoma, Experimental*/therapy , Oncolytic Viruses*/genetics, Animals ; Cell Line, Tumor ; Humans ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Janus Kinases/genetics ; Janus Kinases/metabolism ; Mice ; Mutation ; STAT Transcription Factors/genetics ; STAT Transcription Factors/metabolism ; Signal Transduction
مستخلص: 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 .
(©2021 American Association for Cancer Research.)
التعليقات: Comment in: Clin Cancer Res. 2021 Jun 15;27(12):3278-3279. (PMID: 33849964)
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المشرفين على المادة: 0 (Immune Checkpoint Inhibitors)
0 (STAT Transcription Factors)
EC 2.7.10.2 (Janus Kinases)
تواريخ الأحداث: Date Created: 20210217 Date Completed: 20220407 Latest Revision: 20220613
رمز التحديث: 20221213
DOI: 10.1158/1078-0432.CCR-20-3365
PMID: 33593882
قاعدة البيانات: MEDLINE
الوصف
تدمد:1557-3265
DOI:10.1158/1078-0432.CCR-20-3365