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白细胞介素-10受体信号促进维持抗肿瘤免疫的PD-1int TCF-1+ CD8+ T细胞群
作者:小柯机器人 发布时间:2021/12/11 14:55:04

德国海德堡肿瘤研究中心 Martina Seiffert 和 Bola S. Hanna 共同合作取得重要进展。他们研究发现白细胞介素-10 (IL-10) 受体信号促进维持抗肿瘤免疫的 PD-1int TCF-1+ CD8+ T 细胞群。相关工作于2021年12月7日在线发表在《免疫学》杂志上。

在这里,研究人员利用慢性淋巴细胞白血病 (chronic lymphocytic leukemia, CLL) 模型探究了调节 T 细胞耗竭的微环境信号。单细胞分析鉴定出了 PD-1hi  ( high PD-1 expression)亚群,在疾病进展过程中,这群功能受损的 CD8+ T 细胞会在次级淋巴器官中累积。另外研究人员还鉴定出了一个功能完备的PD-1int ( intermediate PD-1 expression)亚群。随着 Il10rb 或 Stat3 的缺失,PD-1int TCF-1+ CD8+ T 细胞的数量会降低,从而导致 PD-1hi 细胞的累积,加速肿瘤的进展。

从机制上讲,IL-10R (IL-10 or IL-10 receptor)信号的抑制改变了染色质的可接近性并破坏了转录因子 NFAT 和 AP-1 之间的协同作用,促进了一个独特的 NFAT 相关事件。在 CLL 模型和乳腺癌患者中,IL10 的低表达或 IL-10R-STAT3 信号缺失与 CD8+ T 细胞耗竭频率增加以及低生存率有关。因此,PD-1hi,功能耗竭的 CD8+ T 细胞和功能完备的 PD-1int TCF-1+ CD8+ T细胞之间的平衡受到细胞内在的 IL-10R 信号传导的调控,IL-10R 信号对免疫治疗有影响。

据介绍,T 细胞耗竭限制了抗肿瘤免疫和肿瘤细胞对免疫疗法的反应。

附:英文原文

Title: Interleukin-10 receptor signaling promotes the maintenance of a PD-1int TCF-1+ CD8+ T cell population that sustains anti-tumor immunity

Author: Bola S. Hanna, Laura Llaó-Cid, Murat Iskar, Philipp M. Roessner, Lara C. Klett, John K.L. Wong, Yashna Paul, Nikolaos Ioannou, Selcen ztürk, Norman Mack, Verena Kalter, Dolors Colomer, Elías Campo, Johannes Bloehdorn, Stephan Stilgenbauer, Sascha Dietrich, Manfred Schmidt, Richard Gabriel, Karsten Rippe, Markus Feuerer, Alan G. Ramsay, Peter Lichter, Marc Zapatka, Martina Seiffert

Issue&Volume: 2021-12-07

Abstract: T cell exhaustion limits anti-tumor immunity and responses to immunotherapy. Here,we explored the microenvironmental signals regulating T cell exhaustion using a modelof chronic lymphocytic leukemia (CLL). Single-cell analyses identified a subset ofPD-1hi, functionally impaired CD8+ T cells that accumulated in secondary lymphoid organs during disease progressionand a functionally competent PD-1int subset. Frequencies of PD-1int TCF-1+ CD8+ T cells decreased upon Il10rb or Stat3 deletion, leading to accumulation of PD-1hi cells and accelerated tumor progression. Mechanistically, inhibition of IL-10R signalingaltered chromatin accessibility and disrupted cooperativity between the transcriptionfactors NFAT and AP-1, promoting a distinct NFAT-associated program. Low IL10 expression or loss of IL-10R-STAT3 signaling correlated with increased frequenciesof exhausted CD8+ T cells and poor survival in CLL and in breast cancer patients. Thus, balance betweenPD-1hi, exhausted CD8+ T cells and functional PD-1int TCF-1+ CD8+ T cells is regulated by cell-intrinsic IL-10R signaling, with implications for immunotherapy.

DOI: 10.1016/j.immuni.2021.11.004

Source: https://www.cell.com/immunity/fulltext/S1074-7613(21)00495-7

期刊信息

Immunity:《免疫》,创刊于1994年。隶属于细胞出版社,最新IF:21.522
官方网址:https://www.cell.com/immunity/home
投稿链接:https://www.editorialmanager.com/immunity/default.aspx