| Title: | Genetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma |
| Journal: | Proceedings of the National Academy of Sciences of the United States of America |
| Published: | 28 May 2021 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/34050029/ |
| DOI: | https://doi.org/10.1073/pnas.2104504118 |
| Citations: | 51 (34 in last 2 years) as of 8 Aug 2024 |
Publication 12870
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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 lymphomagenesis, 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.</p>
9 Keywords
- Cell Line, Tumor
- Cell Transformation, Neoplastic
- Cytidine Deaminase
- Gene Silencing
- Histocompatibility Antigens Class I
- Humans
- Lymphoma, Large B-Cell, Diffuse
- Proto-Oncogene Proteins c-bcl-6
- beta 2-Microglobulin
20 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 47884 | Identification of genomic and microenvironmental factors in high-risk populations for pancreatic cancer |
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