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

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

doi:10.1016/j.immuni.2020.11.002

Abstract

Tumors frequently subvert major histocompatibility complex class I (MHC-I) peptide presentation to evade CD8+ Tcell 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.

Highlights

CD8+ T cells surveil for malignant or pathogen-infected cells by probing major histocompatibility complex class I (MHC-I), a cell surface heterotrimer constitutively expressed on virtually all nucleated cells in jawed vertebrates
Peptide-loaded MHC-I is trafficked to the plasma membrane where it can be scanned by T cells via their clonally restricted T cell receptors (TCRs), which are selected for their ability to recognize self MHC bound to peptides perceived as non-self
Genome-wide CRISPR-Cas9 Screens Identify Regulators of MHC-I in diffuse large B cell lymphomas (DLBCLs) We identified genes that regulate surface MHC-I in DLBCL by using four patient-derived lymphoma cell lines representing both Germinal center B cell-like (GCB)- and Activated B cell-like (ABC)-classified tumors

Summary

Introduction

CD8+ T cells surveil for malignant or pathogen-infected cells by probing major histocompatibility complex class I (MHC-I), a cell surface heterotrimer constitutively expressed on virtually all nucleated cells in jawed vertebrates. MHC-I complexes are formed in the endoplasmic reticulum (ER) by association of polymorphic heavy chains with b2 microglobulin, subsequently loaded with high-affinity peptides transported from the cytoplasm by the peptide transporter TAP. Peptide-loaded MHC-I is trafficked to the plasma membrane where it can be scanned by T cells via their clonally restricted T cell receptors (TCRs), which are selected for their ability to recognize self MHC bound to peptides perceived as non-self. Debate had raged for decades regarding the ability of T cells to recognize cancer cells as non-self. Immunogenic cancer-associated peptides can arise from mutations in tumor cell genes (Yadav et al, 2014), enhanced transcription or translation of non-tolerized reading frames (Laumont et al, 2018), and post-translational modifications of peptides (Liepe et al, 2019)

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Conclusion