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dc.contributor.authorKriegsman, Barry
dc.contributor.authorVangala, Pranitha
dc.contributor.authorChen, Benjamin J.
dc.contributor.authorMeraner, Paul
dc.contributor.authorBrass, Abraham L.
dc.contributor.authorGarber, Manuel
dc.contributor.authorRock, Kenneth L.
dc.date2022-08-11T08:07:59.000
dc.date.accessioned2022-08-23T15:38:06Z
dc.date.available2022-08-23T15:38:06Z
dc.date.issued2019-10-01
dc.date.submitted2019-09-25
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.issn0022-1767 (Linking)
dc.identifier.doi10.4049/jimmunol.1900475
dc.identifier.pmid31471524
dc.identifier.urihttp://hdl.handle.net/20.500.14038/25863
dc.description.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.
dc.language.isoen_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.urlhttps://doi.org/10.4049/jimmunol.1900475
dc.subjectAmino Acids, Peptides, and Proteins
dc.subjectBiochemistry, Biophysics, and Structural Biology
dc.subjectCancer Biology
dc.subjectComputational Biology
dc.subjectGenetic Phenomena
dc.subjectHemic and Immune Systems
dc.subjectImmunity
dc.subjectImmunopathology
dc.subjectImmunoprophylaxis and Therapy
dc.subjectNeoplasms
dc.titleFrequent Loss of IRF2 in Cancers Leads to Immune Evasion through Decreased MHC Class I Antigen Presentation and Increased PD-L1 Expression
dc.typeJournal Article
dc.source.journaltitleJournal of immunology (Baltimore, Md. : 1950)
dc.source.volume203
dc.source.issue7
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/bioinformatics_pubs/156
dc.identifier.contextkey15424796
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.submissionpathbioinformatics_pubs/156
dc.contributor.departmentGarber Lab
dc.contributor.departmentDepartment of Medicine, Gastroenterology Division
dc.contributor.departmentDepartment of Microbiology and Physiological Systems
dc.contributor.departmentDepartment of Bioinformatics and Integrative Biology
dc.contributor.departmentDepartment of Pathology
dc.source.pages1999-2010


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