B细胞非霍奇金淋巴瘤内肿瘤调节性T细胞的多样性。
Diversity of intratumoral regulatory T cells in B-cell non-Hodgkin lymphoma.
发表日期：2023 Sep 11
作者：
Ivana Spasevska, Ankush Sharma, Chloé Beate Steen, Sarah E Josefsson, Yngvild Nuvin Blaker, Arne Kolstad, Even H Rustad, Saskia Meyer, Kathrine T Isaksen, Stalin Chellappa, Kushi Kushekhar, Klaus Beiske, Mette S Førsund, Signe Spetalen, Harald Holte, Bjorn Ostenstad, Marianne Brodtkorb, Eva K Kimby, Johanna Olweus, Kjetil Taskén, Aaron M Newman, Susanne Lorenz, Erlend B Smeland, Ash A Alizadeh, Kanutte Huse, June Helen Myklebust
来源：
Blood Advances
摘要：
肿瘤浸润性调节性T细胞（Tregs）是免疫抑制的肿瘤微环境的一部分。虽然进行了大量研究，但在B细胞性非霍奇金淋巴瘤（B-NHL）中，肿瘤浸润的Tregs的预后影响仍不清楚。新近研究表明Tregs的表型和抑制能力存在显著的异质性，强调了了解Treg多样性的重要性以及需要其他标记物来鉴定高度抑制性的Tregs。在这里，我们应用了单细胞RNA测序和TCR测序结合高维细胞学方法，来解析弥漫性大B细胞淋巴瘤（DLBCL）和滤泡淋巴瘤（FL）中肿瘤内Tregs的异质性，与非恶性扁桃体组织进行对比。我们鉴别出三种不同的Treg转录状态：静止状态、活化状态和非常规LAG3+FOXP3- Treg。在B-NHL肿瘤中富集了活化型Tregs，其中几个检查点受体共表达，并且与静止型Treg相比具有更强的免疫抑制活性。在FL中，活化型Tregs与CD4+和CD8+ T细胞的近距离接触最多。此外，我们采用一种计算方法开发了独特的基因签名矩阵，用于统计每个Treg亚群在批量基因表达数据的队列中的数量。在两个独立的FL队列中，活化型Tregs是主要亚群，并且高含量与不良预后相关。本研究证明，浸润NHL肿瘤的Tregs在转录和功能上具有多样性。高度免疫抑制的活化型Tregs富集于肿瘤组织中，但在周围血液中不存在。我们的数据表明，深入了解B-NHL中的Treg异质性可能为合理的药物设计开辟新途径，从而有助于选择性靶向改善抗肿瘤免疫。版权所有 © 2023 年美国血液学会。
Tumor-infiltrating regulatory T cells (Tregs) contribute to an immunosuppressive tumor microenvironment. Despite extensive studies, the prognostic impact of tumor-infiltrating Tregs in B-cell non-Hodgkin lymphomas (B-NHL) remains unclear. Emerging studies suggest substantial heterogeneity in the phenotypes and suppressive capacities of Tregs, emphasizing the importance of understanding Treg diversity and the need for additional markers to identify highly suppressive Tregs. Here, we applied single-cell RNA sequencing and TCR sequencing combined with high-dimensional cytometry to decipher the heterogeneity of intratumoral Tregs in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL), compared with non-malignant tonsillar tissue. We identified three distinct transcriptional states of Tregs; resting, activated and unconventional LAG3+FOXP3- Tregs. Activated Tregs were enriched in B-NHL tumors, co-expressed several checkpoint receptors and had stronger immunosuppressive activity compared with resting Tregs. In FL, activated Tregs were found in closer proximity to CD4+ and CD8+ T cells than other cell types. Furthermore, we used a computational approach to develop unique gene signature matrices which were used to enumerate each Treg subset in cohorts with bulk gene expression data. In two independent FL cohorts, activated Tregs was the major subset, and high abundance was associated with adverse outcome. This study demonstrates that Tregs infiltrating NHL tumors are transcriptionally and functionally diverse. Highly immunosuppressive activated Tregs were enriched in tumor tissue but absent in peripheral blood. Our data suggest that a deeper understanding of Treg heterogeneity in B-NHL could open new paths for rational drug design, facilitating selective targeting to improve anti-tumor immunity.Copyright © 2023 American Society of Hematology.