TitleMolecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition.
Publication TypeJournal Article
Year of Publication2019
AuthorsEnnishi, 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., and Steidl Christian
JournalCancer Discov
Volume9
Issue4
Pagination546-563
Date Published2019 04
ISSN2159-8290
KeywordsAnimals, Cell Line, Tumor, Enhancer of Zeste Homolog 2 Protein, Gene Expression Regulation, Neoplastic, Humans, Mice, Prognosis
Abstract

<p>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...</p>

DOI10.1158/2159-8290.CD-18-1090
Alternate JournalCancer Discov
PubMed ID30705065
Grant ListFDN-143288 / / CIHR / Canada