Olschewski Vito, Witte Hanno M, Bernard Veronica, Steinestel Konrad, Peter Wolfgang, Merz Hartmut, Rieken Johannes, Biersack Harald, von Bubnoff Nikolas, Feller Alfred C, Gebauer Niklas
Department of Haematology and Oncology, University Hospital of Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany.
Department of Hematology and Oncology, Federal Armed Forces Hospital Ulm, Oberer Eselsberg 40, 89081 Ulm, Germany.
Cancers (Basel). 2021 Feb 20;13(4):887. doi: 10.3390/cancers13040887.
High-grade B-cell lymphoma, with and and/or rearrangements (double/triple-hit high grade B-cell lymphoma, HGBL-DH/TH) constitutes a provisional entity among B-cell malignancies with an aggressive behavior and dire prognosis. While evidence for the essential prognostic role of the composition of the tumor-microenvironment (TME) in hematologic malignancies is growing, its prognostic impact in HGBL-DH/TH remains unknown. In this study, we outline the adaptive immune response in a cohort of 47 HGBL-DH/TH and 27 triple-negative diffuse large B-cell lymphoma (tnDLBCL) patients in a large-scale, next-generation sequencing (NGS) investigation of the T-cell receptor (TCR) β-chain repertoire and supplement our findings with data on the Glasgow-Prognostic Score (GPS) at diagnosis, as a score-derived measure of systemic inflammation. We supplement these studies with an immunophenotypic investigation of the TME. Our findings demonstrate that the clonal architecture of the TCR repertoire of HGBL-DH/TH differs significantly from tnDLBCL. Moreover, several entity-exclusive clonotypes, suggestive of tumor-neoantigen selection are identified. Additionally, both productive clonality and percentage of maximum frequency clone as measures of TCR repertoire diversity and tumor-directed activity of the adaptive immune system had significant impact on overall survival (OS; productive clonality: = 0.0273; HR: 2.839; CI: 1.124-7.169; maximum productive frequency: = 0.0307; HR: 2.167; CI: 1.074-4.370) but not PFS (productive clonality: = 0.4459; maximum productive frequency: = 0.5567) in HGBL-DH/TH patients, while GPS was a significant predictor of both OS and PFS (OS: < 0.0001; PFS: = 0.0002). Subsequent multivariate analysis revealed GPS and the revised international prognostic index (R-IPI) to be the only prognosticators holding significant impact for OS (GPS: = 0.038; R-IPI: = 0.006) and PFS (GPS: = 0.029; R-IPI: = 0.006) in HGBL-DH/TH. Through the identification of expanded, recurrent and entity-exclusive TCR-clonotypes we provide indications for a distinct subset of tumor-neoantigenic elements exclusively shared among HGBL-DH/TH. Further, we demonstrate an adverse prognostic role for both systemic inflammation and uniform adaptive immune response.
伴有 、 及/或 重排的高级别B细胞淋巴瘤（双打击/三打击高级别B细胞淋巴瘤，HGBL-DH/TH）是B细胞恶性肿瘤中的一个临时实体，具有侵袭性生物学行为和不良预后。虽然肿瘤微环境（TME）组成在血液系统恶性肿瘤中的重要预后作用的证据越来越多，但其在HGBL-DH/TH中的预后影响仍不清楚。在本研究中，我们在一项对T细胞受体（TCR）β链库进行大规模下一代测序（NGS）的研究中，概述了47例HGBL-DH/TH患者和27例三阴性弥漫性大B细胞淋巴瘤（tnDLBCL）患者队列中的适应性免疫反应，并用诊断时的格拉斯哥预后评分（GPS）数据补充我们的发现，GPS是一种基于评分的全身炎症指标。我们通过对TME进行免疫表型研究来补充这些研究。我们的发现表明，HGBL-DH/TH的TCR库的克隆结构与tnDLBCL有显著差异。此外，还鉴定出了几种提示肿瘤新抗原选择的实体特异性克隆型。此外，作为TCR库多样性和适应性免疫系统肿瘤定向活性指标的有效克隆性和最大频率克隆百分比均对HGBL-DH/TH患者的总生存期（OS；有效克隆性： = 0.0273；HR：2.839；CI：1.124 - 7.169；最大有效频率： = 0.0307；HR：2.167；CI：1.074 - 4.370）有显著影响，但对无进展生存期（PFS）无影响（有效克隆性： = 0.4459；最大有效频率： = 0.5567），而GPS是OS和PFS的显著预测指标（OS： < 0.0001；PFS： = 0.0002）。随后的多变量分析显示，GPS和修订后的国际预后指数（R-IPI）是对HGBL-DH/TH患者的OS（GPS： = 0.038；R-IPI： = 0.006）和PFS（GPS： = 0.029；R-IPI： = 0.006）具有显著影响的唯一预后因素。通过鉴定扩增的、复发的和实体特异性的TCR克隆型，我们为HGBL-DH/TH中专门共享的独特肿瘤新抗原元件子集提供了线索。此外，我们证明了全身炎症和一致的适应性免疫反应均具有不良预后作用。
