匹兹堡大学医学院Dario A. A. Vignali课题组的一项最新研究发现了调节性T细胞通过其适应可塑性产生分别分泌IL-10⁺和IL-35⁺的细胞亚群来共同促进肿瘤T细胞耗竭。2019年6月，国际知名学术期刊《Nature Immunology》发表了这一成果。

通过单细胞测序技术，该团队发现细胞因子IL-10和IL-35(Ebi3IL-12α heterodimer)由肿瘤微环境中不同的T_reg细胞亚群分别表达。这些细胞亚群通过调节多个抑制性受体以及其他CD8阳性T细胞的耗竭相关特征基因的表达来共同促进肿瘤内T细胞耗竭。尽管都与BLIMP1受体结合，IL-10和IL-35却分别对效应T细胞和记忆T细胞的命运有不同的影响。因此，这两个细胞因子在抗肿瘤免疫调节中功能部分重叠但却不冗余。这项研究工作首次揭示了由不同T_reg亚群细胞分泌的IL-10和IL-35如何共同来促进CD8阳性肿瘤浸润T细胞的耗竭，由此阻碍了抗肿瘤免疫的功能发挥。

据介绍，调节性T细胞（T_reg细胞）参与维持宿主自身免疫耐受，但是也成为了癌症免疫疗法的主要障碍。T_reg细胞通过调节肿瘤浸润淋巴细胞表面的抑制性受体表达来阻碍抗肿瘤免疫，然而，其背后的介导者与机制仍不清楚。

附：英文原文

Title: Adaptive plasticity of IL-10⁺ and IL-35⁺ T reg cells cooperatively promotes tumor T cell exhaustion

Author: Deepali V. Sawant, Hiroshi Yano, Maria Chikina, Qianxia Zhang, Mengting Liao, Chang Liu, Derrick J. Callahan, Zhe Sun, Tao Sun, Tracy Tabib, Arjun Pennathur, David B. Corry, James D. Luketich, Robert Lafyatis, Wei Chen, Amanda C. Poholek, Tullia C. Bruno, Creg J. Workman, Dario A. A. Vignali

Issue&Volume: Volume 20 Issue 6, June 2019

Abstract: Regulatory T cells (T_reg cells) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Treg cells subvert beneficial anti-tumor immunity by modulating inhibitory receptor expression on tumor-infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms have remained elusive. Here, we found that the cytokines IL-10 and IL-35 (Ebi3IL-12α heterodimer) were divergently expressed by Treg cell subpopulations in the tumor microenvironment (TME) and cooperatively promoted intratumoral T cell exhaustion by modulating several inhibitory receptor expression and exhaustion-associated transcriptomic signature of CD8⁺ TILs. While expression of BLIMP1 (encoded by Prdm1) was a common target, IL-10 and IL-35 differentially affected effector T cell versus memory T cell fates, respectively, highlighting their differential, partially overlapping but non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated cooperative roles for Treg cell-derived IL-10 and IL-35 in promoting BLIMP1-dependent exhaustion of CD8⁺ TILs that limits effective anti-tumor immunity.

DOI: 10.1038/s41590-019-0346-9

Source:https://www.nature.com/articles/s41590-019-0346-9