American Association for Cancer Research
21598290cd181090-sup-208979_2_supp_5279925_plcrzq.xlsx (44.44 kB)

Supplementary Table S8-9 from Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

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posted on 2023-04-03, 21:43 authored by Daisuke Ennishi, Katsuyoshi Takata, Wendy Béguelin, Gerben Duns, Anja Mottok, Pedro Farinha, Ali Bashashati, Saeed Saberi, Merrill Boyle, Barbara Meissner, Susana Ben-Neriah, Bruce W. Woolcock, Adèle Telenius, Daniel Lai, Matt Teater, Robert Kridel, Kerry J. Savage, Laurie H. Sehn, Ryan D. Morin, Marco A. Marra, Sohrab P. Shah, Joseph M. Connors, Randy D. Gascoyne, David W. Scott, Ari M. Melnick, Christian Steidl

Prognostic values of MHC expression


Terry Fox Research Institute

Michael Smith Foundation for Health Research

Canadian Institutes of Health Research

Japanese Society for The Promotion of Science.

Uehara Memorial Foundation

British Columbia Cancer Foundation

Genome Canada, Genome British Columbia




German Cancer Aid




We performed a genomic, transcriptomic, and immunophenotypic study of 347 patients with diffuse large B-cell lymphoma (DLBCL) to uncover the molecular basis underlying acquired deficiency of MHC expression. Low MHC-II expression defines tumors originating from the centroblast-rich dark zone of the germinal center (GC) that was associated with inferior prognosis. MHC-II–deficient tumors were characterized by somatically acquired gene mutations reducing MHC-II expression and a lower amount of tumor-infiltrating lymphocytes. In particular, we demonstrated a strong enrichment of EZH2 mutations in both MHC-I– and MHC-II–negative primary lymphomas, and observed reduced MHC expression and T-cell infiltrates in murine lymphoma models expressing mutant Ezh2Y641. Of clinical relevance, EZH2 inhibitors significantly restored MHC expression in EZH2-mutated human DLBCL cell lines. Hence, our findings suggest a tumor progression model of acquired immune escape in GC-derived lymphomas and pave the way for development of complementary therapeutic approaches combining immunotherapy with epigenetic reprogramming. We demonstrate how MHC-deficient lymphoid tumors evolve in a cell-of-origin–specific context. Specifically, EZH2 mutations were identified as a genetic mechanism underlying acquired MHC deficiency. The paradigmatic restoration of MHC expression by EZH2 inhibitors provides the rationale for synergistic therapies combining immunotherapies with epigenetic reprogramming to enhance tumor recognition and elimination.See related commentary by Velcheti et al., p. 472.This article is highlighted in the In This Issue feature, p. 453

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