Frequent Loss of IRF2 in Cancers Leads to Immune Evasion through Decreased MHC Class I Antigen Presentation and Increased PD-L1 Expression
Chen, Benjamin J.
Brass, Abraham L.
Rock, Kenneth L.
UMass Chan AffiliationsGarber Lab
Department of Medicine, Gastroenterology Division
Department of Microbiology and Physiological Systems
Department of Bioinformatics and Integrative Biology
Department of Pathology
KeywordsAmino Acids, Peptides, and Proteins
Biochemistry, Biophysics, and Structural Biology
Hemic and Immune Systems
Immunoprophylaxis and Therapy
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AbstractTo arise and progress, cancers need to evade immune elimination. Consequently, progressing tumors are often MHC class I (MHC-I) low and express immune inhibitory molecules, such as PD-L1, which allows them to avoid the main antitumor host defense, CD8(+) T cells. The molecular mechanisms that led to these alterations were incompletely understood. In this study, we identify loss of the transcription factor IRF2 as a frequent underlying mechanism that leads to a tumor immune evasion phenotype in both humans and mice. We identified IRF2 in a CRISPR-based forward genetic screen for genes that controlled MHC-I Ag presentation in HeLa cells. We then found that many primary human cancers, including lung, colon, breast, prostate, and others, frequently downregulated IRF2. Although IRF2 is generally known as a transcriptional repressor, we found that it was a transcriptional activator of many key components of the MHC-I pathway, including immunoproteasomes, TAP, and ERAP1, whose transcriptional control was previously poorly understood. Upon loss of IRF2, cytosol-to-endoplasmic reticulum peptide transport and N-terminal peptide trimming become rate limiting for Ag presentation. In addition, we found that IRF2 is a repressor of PD-L1. Thus, by downregulating a single nonessential gene, tumors become harder to see (reduced Ag presentation), more inhibitory (increased checkpoint inhibitor), and less susceptible to being killed by CD8(+) T cells. Importantly, we found that the loss of Ag presentation caused by IRF2 downregulation could be reversed by IFN-stimulated induction of the transcription factor IRF1. The implication of these findings for tumor progression and immunotherapy are discussed.
J Immunol. 2019 Oct 1;203(7):1999-2010. doi: 10.4049/jimmunol.1900475. Epub 2019 Aug 30. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/25863