Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

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 g...

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Published in:Cancer discovery Vol. 9; no. 4; p. 546
Main Authors: Ennishi, Daisuke, Takata, Katsuyoshi, Béguelin, Wendy, Duns, Gerben, Mottok, Anja, Farinha, Pedro, Bashashati, Ali, Saberi, Saeed, Boyle, Merrill, Meissner, Barbara, Ben-Neriah, Susana, Woolcock, Bruce W, Telenius, Adèle, Lai, Daniel, Teater, Matt, Kridel, Robert, Savage, Kerry J, Sehn, Laurie H, Morin, Ryan D, Marra, Marco A, Shah, Sohrab P, Connors, Joseph M, Gascoyne, Randy D, Scott, David W, Melnick, Ari M, Steidl, Christian
Format: Journal Article
Language:English
Published: United States 01.04.2019
Subjects:
Animals
Cell Line, Tumor
Enhancer of Zeste Homolog 2 Protein - genetics
Gene Expression Regulation, Neoplastic - genetics
Humans
Mice
Prognosis
ISSN:2159-8290, 2159-8290
Online Access:Get more information
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Summary: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 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 . Of clinical relevance, EZH2 inhibitors significantly restored MHC expression in -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. SIGNIFICANCE: We demonstrate how MHC-deficient lymphoid tumors evolve in a cell-of-origin-specific context. Specifically, 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. . .
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ISSN:2159-8290
2159-8290
DOI:10.1158/2159-8290.CD-18-1090