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

TitleGenetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma.
Publication TypeJournal Article
Year of Publication2021
AuthorsFangazio M, Ladewig E, Gomez K, Garcia-Ibanez L, Kumar R, Teruya-Feldstein J, Rossi D, Filip I, Pan-Hammarström Q, Inghirami G, Boldorini R, Ott G, Staiger AM, Chapuy B, Gaidano G, Bhagat G, Basso K, Rabadan R, Pasqualucci L, Dalla-Favera R
JournalProc Natl Acad Sci U S A
Volume118
Issue22
Date Published2021 Jun 01
ISSN1091-6490
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 and the loci in 80% (34 of 42) of MHC-I tumors. Furthermore, 70% (22 of 32) of MHC-I DLBCLs harbored monoallelic HLA-I genetic alterations (MHC-I), indicating allele-specific inactivation. MHC-I and MHC-I cases harbored significantly higher mutational burden and inferred neoantigen load, suggesting potential coselection of loss and sustained neoantigen production. Notably, the analysis of >500,000 individuals across different cancer types revealed common germline 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 lymphomagenesis, suggesting that additional events are needed to license immune evasion. These results suggest a multistep process of loss in DLBCL development including both germline and somatic events, and have direct implications for the pathogenesis and immunotherapeutic targeting of this disease.

DOI10.1073/pnas.2104504118
Alternate JournalProc Natl Acad Sci U S A
PubMed ID34050029
PubMed Central IDPMC8179151
Grant ListT32 GM007367 / GM / NIGMS NIH HHS / United States
R01 CA172492 / CA / NCI NIH HHS / United States
U01 CA243073 / CA / NCI NIH HHS / United States
R35 CA210105 / CA / NCI NIH HHS / United States
U54 CA193313 / CA / NCI NIH HHS / United States
P30 CA013696 / CA / NCI NIH HHS / United States
K00 CA212478 / CA / NCI NIH HHS / United States
Related Faculty: 
Giorgio Inghirami, M.D.

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