Frequent Loss of IRF2 in Cancers Leads to Immune Evasion through Decreased MHC Class I Antigen Presentation and Increased PD-L1 Expression
dc.contributor.author | Kriegsman, Barry | |
dc.contributor.author | Vangala, Pranitha | |
dc.contributor.author | Chen, Benjamin J. | |
dc.contributor.author | Meraner, Paul | |
dc.contributor.author | Brass, Abraham L. | |
dc.contributor.author | Garber, Manuel | |
dc.contributor.author | Rock, Kenneth L. | |
dc.date | 2022-08-11T08:07:59.000 | |
dc.date.accessioned | 2022-08-23T15:38:06Z | |
dc.date.available | 2022-08-23T15:38:06Z | |
dc.date.issued | 2019-10-01 | |
dc.date.submitted | 2019-09-25 | |
dc.identifier.citation | <p>J Immunol. 2019 Oct 1;203(7):1999-2010. doi: 10.4049/jimmunol.1900475. Epub 2019 Aug 30. <a href="https://doi.org/10.4049/jimmunol.1900475">Link to article on publisher's site</a></p> | |
dc.identifier.issn | 0022-1767 (Linking) | |
dc.identifier.doi | 10.4049/jimmunol.1900475 | |
dc.identifier.pmid | 31471524 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/25863 | |
dc.description.abstract | 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. | |
dc.language.iso | en_US | |
dc.relation | <p><a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=31471524&dopt=Abstract">Link to Article in PubMed</a></p> | |
dc.relation.url | https://doi.org/10.4049/jimmunol.1900475 | |
dc.subject | Amino Acids, Peptides, and Proteins | |
dc.subject | Biochemistry, Biophysics, and Structural Biology | |
dc.subject | Cancer Biology | |
dc.subject | Computational Biology | |
dc.subject | Genetic Phenomena | |
dc.subject | Hemic and Immune Systems | |
dc.subject | Immunity | |
dc.subject | Immunopathology | |
dc.subject | Immunoprophylaxis and Therapy | |
dc.subject | Neoplasms | |
dc.title | Frequent Loss of IRF2 in Cancers Leads to Immune Evasion through Decreased MHC Class I Antigen Presentation and Increased PD-L1 Expression | |
dc.type | Journal Article | |
dc.source.journaltitle | Journal of immunology (Baltimore, Md. : 1950) | |
dc.source.volume | 203 | |
dc.source.issue | 7 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/bioinformatics_pubs/156 | |
dc.identifier.contextkey | 15424796 | |
html.description.abstract | <p>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.</p> | |
dc.identifier.submissionpath | bioinformatics_pubs/156 | |
dc.contributor.department | Garber Lab | |
dc.contributor.department | Department of Medicine, Gastroenterology Division | |
dc.contributor.department | Department of Microbiology and Physiological Systems | |
dc.contributor.department | Department of Bioinformatics and Integrative Biology | |
dc.contributor.department | Department of Pathology | |
dc.source.pages | 1999-2010 |