Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma Journal Article
| Authors: | Fangazio, 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, A. M.; Chapuy, B.; Gaidano, G.; Bhagat, G.; Basso, K.; Rabadan, R.; Pasqualucci, L.; Dalla-Favera, R. |
| Article Title: | Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma |
| 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. © 2021 National Academy of Sciences. All rights reserved. |
| Keywords: | controlled study; human tissue; protein expression; unclassified drug; gene mutation; major clinical study; sequence analysis; pathogenesis; nonhuman; cell proliferation; animal cell; mouse; animal tissue; gene; cell survival; disease association; protein depletion; animal experiment; animal model; cohort analysis; gene locus; b lymphocyte; carcinogenesis; homozygosity; somatic hypermutation; antigen; hla antigen class 1; gene inactivation; immunity; genetic disorder; major histocompatibility antigen class 1; dlbcl; hla; immune evasion; immune escape; diffuse large b cell lymphoma; lymphomagenesis; human; male; female; article; whole exome sequencing; neoantigen; mutational burden; deep sequencing; b2m gene; hla i gene; molecular genetic phenomena and functions |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 118 |
| Issue: | 22 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2021-06-01 |
| Start Page: | e2104504118 |
| Language: | English |
| DOI: | 10.1073/pnas.2104504118 |
| PUBMED: | 34050029 |
| PROVIDER: | scopus |
| PMCID: | PMC8179151 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 July 2021 -- Source: Scopus |
