Journal
CANCER DISCOVERY
Volume 9, Issue 4, Pages 546-563Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-18-1090
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Funding
- Terry Fox Research Institute [1023, 1061]
- Michael Smith Foundation for Health Research (MSFHR)
- Canadian Institutes of Health Research (CIHR)
- Japanese Society for The Promotion of Science
- Uehara Memorial Foundation
- British Columbia Cancer Foundation (BCCF)
- Terry Fox Research Institute
- Genome Canada
- Genome British Columbia
- CIHR
- BCCF
- Mildred-Scheel-Cancer-Foundation (German Cancer Aid)
- MSFHR
- Lymphoma Canada
- CIHR New Investigator Award
- CIHR [FDN-143288]
- Michael Smith Foundation for Health Research Investigator award
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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(Y)(641). 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. SIGNIFICANCE: 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.
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