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Genome-Wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I and MHC-II Immunosurveillance in Human Lymphomas

39 Pages Posted: 14 May 2020 Sneak Peek Status: Review Complete

See all articles by Devin Dersh

Devin Dersh

National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Viral Diseases

James D. Phelan

National Institutes of Health, National Cancer Institute

Megan E. Gumina

University of Pennsylvania

Boya Wang

National Institutes of Health, National Cancer Institute

Jesse H. Arbuckle

National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Viral Diseases

Jaroslav Holly

National Institutes of Health - Laboratory of Viral Diseases

Rigel J. Kishton

National Institutes of Health, National Cancer Institute

Tovah E. Markowitz

National Institutes of Health, National Institute of Allergy and Infectious Diseases

Mina O. Seedhom

National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Viral Diseases

Nathan Fridlyand

National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Viral Diseases

George W. Wright

National Institutes of Health, National Cancer Institute

Da Wei Huang

National Institutes of Health, National Cancer Institute

Michele Ceribelli

National Institutes of Health, National Center for Advancing Translational Sciences, Division of Preclinical Innovation

Craig J. Thomas

National Center for Advancing Translational Sciences (NCATS)

Justin B. Lack

National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID)

Nicholas P. Restifo

National Institutes of Health, National Cancer Institute

Thomas M. Kristie

National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Viral Diseases

Louis M. Staudt

National Institutes of Health, National Cancer Institute

Jonathan Yewdell

National Institutes of Health - Laboratory of Viral Diseases

More...

Abstract

Tumors frequently subvert MHC class I (MHC-I) peptide presentation to evade CD8+ T cell immunosurveillance.  To better define the regulatory networks controlling antigen presentation, we employed genome-wide screening in human diffuse large B cell lymphomas (DLBCLs).  This approach revealed dozens of novel genes that positively and negatively modulate MHC-I cell surface levels. Identified genes cluster in multiple pathways including cytokine signaling, mRNA processing, endosomal trafficking, and protein metabolism.  Many genes exhibit lymphoma subtype- or tumor-specific MHC-I regulation, and a majority of primary DLBCL tumors display genetic alterations in multiple regulators.  We establish that the HSP90 co-chaperone SUGT1 is 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, enhances DLBCL MHC-I presentation.  These and other genes represent potential targets for manipulating MHC-I immunosurveillance in cancers, infectious diseases, and autoimmunity.

Keywords: diffuse large B-cell lymphoma, antigen presentation, MHC class I, MHC-I, MHC class II, Immunotherapy, immunoevasion, EZH2, SUGT1, thymidylate synthase

Suggested Citation

Dersh, Devin and Phelan, James D. and Gumina, Megan E. and Wang, Boya and Arbuckle, Jesse H. and Holly, Jaroslav and Kishton, Rigel J. and Markowitz, Tovah E. and Seedhom, Mina O. and Fridlyand, Nathan and Wright, George W. and Huang, Da Wei and Ceribelli, Michele and Thomas, Craig J. and Lack, Justin B. and Restifo, Nicholas P. and Kristie, Thomas M. and Staudt, Louis M. and Yewdell, Jonathan, Genome-Wide Screens Identify Lineage- and Tumor-Specific Genes Modulating MHC-I and MHC-II Immunosurveillance in Human Lymphomas. Available at SSRN: https://ssrn.com/abstract=3584739 or http://dx.doi.org/10.2139/ssrn.3584739
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Devin Dersh

National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Viral Diseases ( email )

Bethesda, MD 20892-9806
United States

James D. Phelan

National Institutes of Health, National Cancer Institute

9609 Medical Center Drive
Bethesda, MD 20892
United States

Megan E. Gumina

University of Pennsylvania

Philadelphia, PA 19104
United States

Boya Wang

National Institutes of Health, National Cancer Institute

9609 Medical Center Drive
Bethesda, MD 20892
United States

Jesse H. Arbuckle

National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Viral Diseases ( email )

Bethesda, MD 20892-9806
United States

Jaroslav Holly

National Institutes of Health - Laboratory of Viral Diseases ( email )

Bethesda, MD 20892-9806
United States

Rigel J. Kishton

National Institutes of Health, National Cancer Institute ( email )

9609 Medical Center Drive
Bethesda, MD 20892
United States

Tovah E. Markowitz

National Institutes of Health, National Institute of Allergy and Infectious Diseases ( email )

Bethesda, MD 20892-9806
United States

Mina O. Seedhom

National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Viral Diseases ( email )

Bethesda, MD 20892-9806
United States

Nathan Fridlyand

National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Viral Diseases ( email )

Bethesda, MD 20892-9806
United States

George W. Wright

National Institutes of Health, National Cancer Institute

9609 Medical Center Drive
Bethesda, MD 20892
United States

Da Wei Huang

National Institutes of Health, National Cancer Institute ( email )

9609 Medical Center Drive
Bethesda, MD 20892
United States

Michele Ceribelli

National Institutes of Health, National Center for Advancing Translational Sciences, Division of Preclinical Innovation ( email )

Rockville, MD
United States

Craig J. Thomas

National Center for Advancing Translational Sciences (NCATS)

31 Center Drive, Suite 3B11
Bethesda, MD 20892-4874
United States

Justin B. Lack

National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIAID) ( email )

Bethesda, MD 20892-9806
United States

Nicholas P. Restifo

National Institutes of Health, National Cancer Institute ( email )

9609 Medical Center Drive
Bethesda, MD 20892
United States

Thomas M. Kristie

National Institutes of Health, National Institute of Allergy and Infectious Diseases, Laboratory of Viral Diseases ( email )

Bethesda, MD 20892-9806
United States

Louis M. Staudt

National Institutes of Health, National Cancer Institute ( email )

9609 Medical Center Drive
Bethesda, MD 20892
United States

Jonathan Yewdell (Contact Author)

National Institutes of Health - Laboratory of Viral Diseases

Bethesda, MD 20892-9806
United States

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