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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-I^NEG tumors. Furthermore, 70% (22 of 32) of MHC-I^POS DLBCLs harbored monoallelic HLA-I genetic alterations (MHC-I^POS/mono), indicating allele-specific inactivation. MHC-I^NEG and MHC-I^POS/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.

SUBMITTER: Fangazio M

PROVIDER: S-EPMC8179151 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Fangazio Marco M Ladewig Erik E Gomez Karen K Garcia-Ibanez Laura L Kumar Rahul R Teruya-Feldstein Julie J Rossi Davide D Filip Ioan I Pan-Hammarström Qiang Q Inghirami Giorgio G Boldorini Renzo R Ott German G Staiger Annette M AM Chapuy Björn B Gaidano Gianluca G Bhagat Govind G Basso Katia K Rabadan Raul R Pasqualucci Laura L Dalla-Favera Riccardo R

Proceedings of the National Academy of Sciences of the United States of America 20210601 22

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 <i>B2M</i> and the <i>HLA-I</i> loci in 8 ...[more]

PMID: 34050029

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Project description:BackgroundRegulatory T cells (Tregs) induce immune responses and may contribute to immune escape in tumors. Accumulation of Tregs in tumors represents a critical barrier to anti-tumor immunity and immunotherapy. However, conflicting results describing the role of Tregs in lymphoma warrant further investigation. The precise features and mechanisms underlying the alteration in Tregs in diffuse large B-cell lymphoma (DLBCL) are not well understood yet. In this study, we analyzed the mechanism underlying the observed alterations in Tregs in DLBCL and examined the effect of Lkb1 expression on the immunosuppressive function of human Tregs.MethodsFlow cytometry and immunofluorescence were used to analyze the proportion of Tregs and effector Tregs in the peripheral blood and lymph nodes of patients with DLBCL and control group. In vitro culture assays were used to analyze the immunosuppressive function of Tregs in the two groups. Transcriptome sequencing was performed to analyze the differentially expressed genes in the two groups, and the transcription level and protein expression of Lkb1 in the two groups were detected using RT-PCR and WES microprotein technology. Lentiviral vectors were constructed to explore the functional changes of Tregs with stable upregulation and downregulation of Lkb1. Finally, a humanized murine lymphoma model was established to study the function of Lkb1 in Tregs in the pathogenesis of DLBCL.ResultsThe number of Tregs was found to be dramatically increased in peripheral blood and tumor tissue in DLBCL patients compared with that in healthy controls, and decreased after treatment. Tregs from DLBCL patients exhibited multiple enhanced functions, including increased inhibition of CD8+cytotoxic T cells (CTL) against tumor cells, enhanced suppression of CD8+CTL secretion of granular enzyme, and suppression of CD8+CTL degranulation. Lkb1 was found to be upregulated in Tregs of DLBCL patients. Furthermore, Lkb1 contributes to Treg immunosuppressive function in DLBCL by regulating the mevalonate pathway. Finally, deletion of Lkb1 in Tregs suppressed tumor growth and promoted anti-tumor immunity in a DLBCL murine model.ConclusionsThese findings confirmed that Lkb1-regulated Tregs are critical for immune escape in DLBCL, which emphasizes that Lkb1 is a potential target for the immunotherapy of DLBCL.

Dataset Information

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

Publications

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

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