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    Frequent Loss of IRF2 in Cancers Leads to Immune Evasion through Decreased MHC Class I Antigen Presentation and Increased PD-L1 Expression

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    Authors
    Kriegsman, Barry
    Vangala, Pranitha
    Chen, Benjamin J.
    Meraner, Paul
    Brass, Abraham L.
    Garber, Manuel
    Rock, Kenneth L.
    UMass Chan Affiliations
    Garber Lab
    Department of Medicine, Gastroenterology Division
    Department of Microbiology and Physiological Systems
    Department of Bioinformatics and Integrative Biology
    Department of Pathology
    Document Type
    Journal Article
    Publication Date
    2019-10-01
    Keywords
    Amino Acids, Peptides, and Proteins
    Biochemistry, Biophysics, and Structural Biology
    Cancer Biology
    Computational Biology
    Genetic Phenomena
    Hemic and Immune Systems
    Immunity
    Immunopathology
    Immunoprophylaxis and Therapy
    Neoplasms
    
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    Link to Full Text
    https://doi.org/10.4049/jimmunol.1900475
    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.
    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.1900475
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/25863
    PubMed ID
    31471524
    Related Resources

    Link to Article in PubMed

    ae974a485f413a2113503eed53cd6c53
    10.4049/jimmunol.1900475
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    Program in Bioinformatics and Integrative Biology Publications

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