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

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. [Display omitted] •Genome-wide screens dramatically expand known regulators of the MHC class I pathway•Human B cell lymphomas exhibit tumor- and subtype-specific modes of immunoevasion•Genes such as SUGT1 co-regulate MHC-I and MHC-II expression•Thymidylate synthase and EZH2 inhibitors enhance tumor peptide presentation MHC class I complexes provide the basis for CD8+ T cell immunosurveillance. Using genome-wide screens, Dersh et al. identify novel genes regulating MHC-I surface expression in human B cell lymphomas. This enabled discovery of drugs that enhance tumor antigen presentation to T cells and can potentially improve immunotherapies.