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

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.

journal_name

Immunity

journal_title

Immunity

authors

Dersh D,Phelan JD,Gumina ME,Wang B,Arbuckle JH,Holly J,Kishton RJ,Markowitz TE,Seedhom MO,Fridlyand N,Wright GW,Huang DW,Ceribelli M,Thomas CJ,Lack JB,Restifo NP,Kristie TM,Staudt LM,Yewdell JW

doi

10.1016/j.immuni.2020.11.002

subject

Has Abstract

pub_date

2021-01-12 00:00:00

pages

116-131.e10

issue

1

eissn

1074-7613

issn

1097-4180

pii

S1074-7613(20)30467-2

journal_volume

54

pub_type

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