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
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We investigated the immunogenomics of 68 lymphoproliferative disorders from 51 immunodeficient (34 post-transplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were large B-cell lymphoma and 25% were primary central nervous system lymphoma, while 40% were EBV+. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden, tumor landscape and tumor microenvironment and prediction of tumor neoepitopes. Both tumor mutational burden (2.2 vs. 3.4/Mb, P=0.001) and numbers of neoepitopes (40 vs. 200, P=0.00019) were lower in EBV+ than in EBV- NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations observed exclusively in EBV+ and immunodeficient NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV- cases but in only half of the EBV+ ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The tumor microenvironment analysis showed higher CD8 T-cell infiltrates in EBV+ versus EBV- NHL, together with a more tolerogenic profile composed of regulatory T cells, 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- patients, offering potential opportunities for future T-cell-based immune therapies.</p>","PeriodicalId":12964,"journal":{"name":"Haematologica","volume":" ","pages":"3615-3630"},"PeriodicalIF":8.2000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11532699/pdf/","citationCount":"0","resultStr":"{\"title\":\"Epstein-Barr virus and immune status imprint the immunogenomics of non-Hodgkin lymphomas occurring in immune-suppressed environments.\",\"authors\":\"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\",\"doi\":\"10.3324/haematol.2023.284332\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Non-Hodgkin lymphomas (NHL) commonly occur in immunodeficient patients, both those infected by human immunodeficiency virus (HIV) and those who have been transplanted, and are often driven by Epstein-Barr virus (EBV) 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 immunodeficient (34 post-transplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were large B-cell lymphoma and 25% were primary central nervous system lymphoma, while 40% were EBV+. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden, tumor landscape and tumor microenvironment and prediction of tumor neoepitopes. Both tumor mutational burden (2.2 vs. 3.4/Mb, P=0.001) and numbers of neoepitopes (40 vs. 200, P=0.00019) were lower in EBV+ than in EBV- NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations observed exclusively in EBV+ and immunodeficient NHL, respectively. 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引用次数: 0
摘要
非霍奇金淋巴瘤(NHL)通常发生在免疫缺陷(ID)患者中,包括艾滋病病毒感染者和移植患者,而且通常是由 EBV 驱动的脑局部淋巴瘤,这就提出了肿瘤免疫原性的问题,这是治疗反应的一个关键问题。我们研究了 51 名 ID 患者(34 名移植后患者,17 名 HIV 感染者)和 17 名免疫功能正常患者的 68 例淋巴组织增生性疾病的免疫基因组学。总体而言,72%为大B细胞淋巴瘤(LBCL),25%为原发性中枢神经系统淋巴瘤(PCNSL),40%为EB病毒阳性。通过肿瘤全外显子组和 RNA 测序以及生物信息学管道,可以分析肿瘤突变负荷(TMB)、肿瘤景观和微环境(TME),并预测肿瘤新表位。无论免疫状态如何,EBV阳性NHL的TMB(2.2 vs 3.4/Mb,p=0.001)和新表位(40 vs 200,p=0.00019)均低于EBV阴性NHL。相反,EBV和免疫状态都会影响肿瘤的突变情况,HNRNPF和STAT3突变分别只在EBV阳性和ID NHL中观察到。在所有EBV阴性病例中都检测到了针对肿瘤新表位的外周血T细胞反应,但只有一半的EBV阳性病例检测到了这种反应,包括针对IgH衍生的MHC-class-II限制性新表位的反应。TME分析表明,在EBV阳性与EBV阴性NHL中,CD8 T细胞浸润率更高,同时Tregs、M2型巨噬细胞的耐受性更强,阴性免疫调节因子的表达增加。我们的研究结果突出表明,免疫缺陷患者NHL的免疫基因组学主要依赖于肿瘤的EBV状态,而EBV阴性患者的T细胞对肿瘤和IgH特异性新表位的识别是保守的,这为未来基于T细胞的免疫疗法提供了潜在的机会。
Epstein-Barr virus and immune status imprint the immunogenomics of non-Hodgkin lymphomas occurring in immune-suppressed environments.
Non-Hodgkin lymphomas (NHL) commonly occur in immunodeficient patients, both those infected by human immunodeficiency virus (HIV) and those who have been transplanted, and are often driven by Epstein-Barr virus (EBV) 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 immunodeficient (34 post-transplant, 17 HIV+) and 17 immunocompetent patients. Overall, 72% were large B-cell lymphoma and 25% were primary central nervous system lymphoma, while 40% were EBV+. Tumor whole-exome and RNA sequencing, along with a bioinformatics pipeline allowed analysis of tumor mutational burden, tumor landscape and tumor microenvironment and prediction of tumor neoepitopes. Both tumor mutational burden (2.2 vs. 3.4/Mb, P=0.001) and numbers of neoepitopes (40 vs. 200, P=0.00019) were lower in EBV+ than in EBV- NHL, regardless of the immune status. In contrast both EBV and the immune status influenced the tumor mutational profile, with HNRNPF and STAT3 mutations observed exclusively in EBV+ and immunodeficient NHL, respectively. Peripheral blood T-cell responses against tumor neoepitopes were detected in all EBV- cases but in only half of the EBV+ ones, including responses against IgH-derived MHC-class-II restricted neoepitopes. The tumor microenvironment analysis showed higher CD8 T-cell infiltrates in EBV+ versus EBV- NHL, together with a more tolerogenic profile composed of regulatory T cells, 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- patients, offering potential opportunities for future T-cell-based immune therapies.
期刊介绍:
Haematologica is a journal that publishes articles within the broad field of hematology. It reports on novel findings in basic, clinical, and translational research.
Scope:
The scope of the journal includes reporting novel research results that:
Have a significant impact on understanding normal hematology or the development of hematological diseases.
Are likely to bring important changes to the diagnosis or treatment of hematological diseases.