USP22 deficiency in melanoma mediates resistance to T cells through IFNγ-JAK1-STAT1 signal axis.

Abstract

Genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated 9 (Cas9)-mediated loss-of-function screens are powerful tools for identifying genes responsible for diverse phenotypes. Here, we perturbed genes in melanoma cells to screen for genes involved in tumor escape from T cell-mediated killing. Multiple interferon gamma (IFNγ) signaling-related genes were enriched in melanoma cells resistant to T cell killing. In addition, deletion of the deubiquitinating protease ubiquitin specific peptidase 22 (USP22) in mouse melanoma (B16-OVA) cells decreased the efficacy of T cell-mediated killing, both in vitro and in vivo, while overexpression enhanced tumor-cell sensitivity to T (OT-I) cell-mediated killing. USP22 deficiency in both mouse and human melanoma cells showed impaired sensitivity to interferon pathway and USP22 was positively correlated with key molecules of interferon pathway in clinical melanoma samples. Mechanistically, USP22 may directly interact with signal transducer and activator of transcription 1 (STAT1), deubiquitinate it, and improve its stability in both human and mouse melanoma cells. Our findings identified a previously unknown function of USP22 and linked the loss of genes in tumor cells that are essential for escaping the effector function of CD8+ T cells during immunotherapy.

• Authors: Min Li, Yanqin Xu, Jie Liang, Hao Lin, Xinyue Qi, Fanlin Li, Ping Han, Yanfeng Gao, Xuanming Yang
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 29 Issue 6 Pg. 2108-2120 (06 02 2021) ISSN: 1525-0024 [Electronic] United States
• PMID: 33601053 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• STAT1 Transcription Factor
• STAT1 protein, human
• Interferon-gamma
• JAK1 protein, human
• Janus Kinase 1
• Ubiquitin Thiolesterase
• Usp22 protein, human

Topics

• Animals
• CRISPR-Cas Systems
• Cell Line, Tumor
• Cytotoxicity, Immunologic (genetics)
• Gene Expression Profiling
• Genome-Wide Association Study
• Humans
• Interferon-gamma (metabolism)
• Janus Kinase 1 (metabolism)
• Melanoma
• Mice
• Protein Stability
• STAT1 Transcription Factor (metabolism)
• Signal Transduction
• T-Lymphocytes (immunology, metabolism)
• Ubiquitin Thiolesterase (deficiency)
• Ubiquitination