Epstein-Barr virus and immune status imprint the immunogenomics of non-Hodgkin lymphomas occurring in immune-suppressed environments.

IF 8.2 1区 医学 Q1 HEMATOLOGY Haematologica Pub Date : 2024-11-01 DOI:10.3324/haematol.2023.284332
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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Abstract

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.

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Epstein-Barr 病毒和免疫状态对免疫抑制环境下发生的非霍奇金淋巴瘤的免疫基因组学产生影响。
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。
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来源期刊
Haematologica
Haematologica 医学-血液学
CiteScore
14.10
自引率
2.00%
发文量
349
审稿时长
3-6 weeks
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.
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