Frequent Loss of IRF2 in Cancers Leads to Immune Evasion through Decreased MHC Class I Antigen Presentation and Increased PD-L1 Expression
Authors
Kriegsman, BarryVangala, Pranitha
Chen, Benjamin J.
Meraner, Paul
Brass, Abraham L.
Garber, Manuel
Rock, Kenneth L.
UMass Chan Affiliations
Garber LabDepartment of Medicine, Gastroenterology Division
Department of Microbiology and Physiological Systems
Department of Bioinformatics and Integrative Biology
Department of Pathology
Document Type
Journal ArticlePublication Date
2019-10-01Keywords
Amino Acids, Peptides, and ProteinsBiochemistry, Biophysics, and Structural Biology
Cancer Biology
Computational Biology
Genetic Phenomena
Hemic and Immune Systems
Immunity
Immunopathology
Immunoprophylaxis and Therapy
Neoplasms
Metadata
Show full item recordAbstract
To 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.Source
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
DOI
10.4049/jimmunol.1900475Permanent Link to this Item
http://hdl.handle.net/20.500.14038/25863PubMed ID
31471524Related Resources
ae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.1900475