Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma

Marco Fangazio, Erik Ladewig, Karen Gomez, Laura Garcia-Ibanez, Rahul Kumar, Julie Teruya-Feldstein, Davide Rossi, Ioan Filip, Qiang Pan-Hammarström, Giorgio Inghirami, Renzo Boldorini, German Ott, Annette M. Staiger, Björn Chapuy, Gianluca Gaidano, Govind Bhagat, Katia Basso, Raul Rabadan, Laura Pasqualucci, Riccardo Dalla-Favera

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Fifty percent of diffuse large B cell lymphoma (DLBCL) cases lack cell-surface expression of the class I major histocompatibility complex (MHC-I), thus escaping recognition by cytotoxic T cells. Here we show that, across B cell lymphomas, loss of MHC-I, but not MHC-II, is preferentially restricted to DLBCL. To identify the involved mechanisms, we performed whole exome and targeted HLA deep-sequencing in 74 DLBCL samples, and found somatic inactivation of B2M and the HLA-I loci in 80% (34 of 42) of MHC-INEG tumors. Furthermore, 70% (22 of 32) of MHC-IPOS DLBCLs harbored monoallelic HLA-I genetic alterations (MHC-IPOS/mono), indicating allele-specific inactivation. MHC-INEG and MHC-IPOS/mono cases harbored significantly higher mutational burden and inferred neoantigen load, suggesting potential coselection of HLA-I loss and sustained neoantigen production. Notably, the analysis of >500,000 individuals across different cancer types revealed common germline HLA-I homozygosity, preferentially in DLBCL. In mice, germinal-center B cells lacking HLA-I expression did not progress to lymphoma and were counterselected in the context of oncogene-driven lymphoma-genesis, suggesting that additional events are needed to license immune evasion. These results suggest a multistep process of HLA-I loss in DLBCL development including both germline and somatic events, and have direct implications for the pathogenesis and immunotherapeutic targeting of this disease.

Original languageEnglish
Article numbere2104504118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number22
DOIs
StatePublished - 1 Jun 2021

Keywords

  • DLBCL
  • HLA
  • Immune evasion

Fingerprint

Dive into the research topics of 'Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma'. Together they form a unique fingerprint.

Cite this