1. Epstein-Barr Virus and immune status imprint the immunogenomics of non-Hodgkin lymphomas occurring in immune-suppressed environments
- Author
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Marine Baron, Karim Labreche, Marianne Veyri, Nathalie Désiré, Amira Bouzidi, Fatou Seck-Thiam, Frédéric Charlotte, Alice Rousseau, Véronique Morin, Cécilia Nakid-Cordero, Baptiste Abbar, Alberto Picca, Marie Le Cann, Noureddine Balegroune, Nicolas Gauthier, Ioannis Theodorou, Mehdi Touat, Véronique Morel, Franck Bielle, Assia Samri, Agusti Alentorn, Marc Sanson, Damien Roos-Weil, Corinne Haioun, Elsa Poullot, Anne Langlois de Septenville, Frédéric Davi, Amélie Guihot, Pierre-Yves Boelle, Véronique Leblond, Florence Coulet, Jean-Philippe Spano, Sylvain Choquet, Brigitte Autran, and IDeATIon study group
- Subjects
Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Non-Hodgkin lymphomas (NHL) commonly occur in immune-deficient (ID) patients, both HIV-infected and transplanted, and are often EBV-driven with cerebral localization, raising the question of tumor immunogenicity, a critical issue for treatment responses. We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 ID (34 posttransplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were Large B Cells Lymphoma (LBCL) and 25% were primary central-nervous-system lymphoma (PCNSL) while 40% were EBV-positive. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden (TMB), tumor landscape and microenvironment (TME) and prediction of tumor neoepitopes. Both TMB (2.2 vs 3.4/Mb, p=0.001) and neoepitopes numbers (40 vs 200, p=0.00019) were lower in EBVpositive than in EBV-negative NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations exclusively observed in EBV-positive and ID NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV-negative cases but in only half EBV-positive ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The TME analysis showed higher CD8 T cell infiltrates in EBVpositive vs EBV-negative NHL, together with a more tolerogenic profile composed of Tregs, type-M2 macrophages and an increased expression of negative immune-regulators. Our results highlight that the immunogenomics of NHL in patients with immunodeficiency primarily relies on the tumor EBV status, while T cell recognition of tumor- and IgH-specific neoepitopes is conserved in EBV-negative patients, offering potential opportunities for future T cell-based immune therapies.
- Published
- 2024
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