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Genome-wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I- and MHC-II-Restricted Immunosurveillance of Human Lymphomas

  1. Author:
    Dersh, Devin
    Phelan, James D
    Gumina, Megan E
    Wang, Boya
    Arbuckle, Jesse H
    Holly, Jaroslav
    Kishton, Rigel J
    Markowitz,Tovah
    Seedhom, Mina O
    Fridlyand, Nathan
    Wright, George W
    Huang, Da Wei
    Ceribelli, Michele
    Thomas, Craig J
    Lack,Justin
    Restifo, Nicholas P
    Kristie, Thomas M
    Staudt, Louis M
    Yewdell, Jonathan W

  2. Author Address

    Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: devin.dersh@nih.gov., Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 USA., NIAID Collaborative Bioinformatics Resource, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Advanced Biomedical Computational Science, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA., Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA; Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Biometric Research Branch, Division of Cancer Diagnosis and Treatment, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA., Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD 20850, USA., Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: jyewdell@niaid.nih.gov.,
    1. Year: 2021
    2. Date: Jan 12
    3. Epub Date: 2020 12 02
  2. Journal: Immunity
    1. 54
    2. 1
    3. Pages: 116-131.e10
  4. Type of Article: Article
  5. ISSN: 1074-7613
  1. Abstract:

    Tumors frequently subvert major histocompatibility complex class I (MHC-I) peptide presentation to evade CD8+ T cell immunosurveillance, though how this is accomplished is not always well defined. To identify the global regulatory networks controlling antigen presentation, we employed genome-wide screening in human diffuse large B cell lymphomas (DLBCLs). This approach revealed dozens of genes that positively and negatively modulate MHC-I cell surface expression. Validated genes clustered in multiple pathways including cytokine signaling, mRNA processing, endosomal trafficking, and protein metabolism. Genes can exhibit lymphoma subtype- or tumor-specific MHC-I regulation, and a majority of primary DLBCL tumors displayed genetic alterations in multiple regulators. We established SUGT1 as a major positive regulator of both MHC-I and MHC-II cell surface expression. Further, pharmacological inhibition of two negative regulators of antigen presentation, EZH2 and thymidylate synthase, enhanced DLBCL MHC-I presentation. These and other genes represent potential targets for manipulating MHC-I immunosurveillance in cancers, infectious diseases, and autoimmunity. Published by Elsevier Inc.

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External Sources

  1. View Full Text
  2. DOI: 10.1016/j.immuni.2020.11.002
  3. PMID: 33271120
  4. View record in Web of Science®
  5. WOS: 000607814000014
  6. PII : S1074-7613(20)30467-2

Library Notes

  1. Fiscal Year: FY2020-2021
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