Molecular and genetic characterization of MHC deficiency identifies ezh2 as therapeutic target for enhancing immune recognition

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. MarraSohrab P. Shah, Joseph M. Connors, Randy D. Gascoyne, David W. Scott, Ari M. Melnick, Christian Steidl

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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 Ezh2 Y641. 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.

Original languageEnglish
Pages (from-to)546-563
Number of pages18
JournalCancer discovery
Volume9
Issue number4
DOIs
Publication statusPublished - Apr 2019
Externally publishedYes

ASJC Scopus subject areas

  • Oncology

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    Ennishi, D., Takata, K., Béguelin, W., Duns, G., Mottok, A., Farinha, P., Bashashati, A., Saberi, S., Boyle, M., Meissner, B., Ben-Neriah, S., Woolcock, B. W., Telenius, A., Lai, D., Teater, M., Kridel, R., Savage, K. J., Sehn, L. H., Morin, R. D., ... Steidl, C. (2019). Molecular and genetic characterization of MHC deficiency identifies ezh2 as therapeutic target for enhancing immune recognition. Cancer discovery, 9(4), 546-563. https://doi.org/10.1158/2159-8290.CD-18-1090