Department of Emergency, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory for Oncogenes and Related Genes, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai 200001, China.
Int Immunopharmacol. 2020 Jan;78:106019. doi: 10.1016/j.intimp.2019.106019. Epub 2019 Nov 24.
Th9 cells are named after their expression of IL-9. Studies in recent years demonstrated that Th9 cells could contribute to antitumor immunity by enhancing the recruitment and activation of mast cells, natural killer cells, CD8 T cells, and dendritic cells in the tumor microenvironment. To determine whether Th9 cells participate in colorectal cancer (CRC), we collected resected tumor samples from 20 CRC patients. In the tumor-infiltrating lymphocytes (TILs), IL-9IL-4 CD4 T cells could be observed and were present at higher frequencies than the IL-9IL-4 and the IL-9IL-4 cells, suggesting that the majority of IL-9-producing TILs were bona fide Th9 cells. IL-9-secreting TILs presented particularly high PD-1 expression directly ex vivo. The expression of IL-9 was significantly reduced with PD-L1-mediated inhibition, which in turn was suppressed by anti-PD-1 blocking. Interestingly, the circulating CD4 T cell compartment in CRC patients also presented Th9 enrichment, characterized by higher IL-9IL-4 and IL-9IL-4 cell frequencies in the CXCR3CCR6 compartment as compared to that in non-cancer controls. Using exogenous TGF-β and IL-4, we were capable of enriching Th9 cells without concurrent enrichment of Th2 cells. Th9-enriched CD4 T cells, but not Th9-non-enriched cells, significantly increased the expansion of activated CD8 T cells, in a manner that was dependent on the expression of IL-9R. In addition, the frequencies of Th9 cells in the tumor were positively correlated with the frequencies of CD8 TILs. Together, we demonstrated that Th9 cells infiltrated CRC tumor, could be regulated via the PD-1/PD-L1 pathway, and could contribute the CD8 T cell expansion.
Th9 细胞因其表达 IL-9 而得名。近年来的研究表明，Th9 细胞可以通过增强肿瘤微环境中肥大细胞、自然杀伤细胞、CD8 T 细胞和树突状细胞的募集和激活来促进抗肿瘤免疫。为了确定 Th9 细胞是否参与结直肠癌（CRC），我们收集了 20 例 CRC 患者的切除肿瘤样本。在肿瘤浸润淋巴细胞（TILs）中，可以观察到 IL-9+IL-4+CD4 T 细胞，其频率高于 IL-9+IL-4 和 IL-9+IL-4 细胞，这表明大多数产生 IL-9 的 TIL 是真正的 Th9 细胞。IL-9 分泌的 TIL 直接在体外表达高水平的 PD-1。PD-L1 介导的抑制显著降低了 IL-9 的表达，而抗 PD-1 阻断又抑制了这种表达。有趣的是，CRC 患者的循环 CD4 T 细胞区室也表现出 Th9 细胞富集，其特征是 CXCR3+CCR6 区室中 IL-9+IL-4 和 IL-9+IL-4 细胞的频率高于非癌症对照。使用外源性 TGF-β 和 IL-4，我们能够在不同时富集 Th2 细胞的情况下富集 Th9 细胞。Th9 细胞富集的 CD4 T 细胞，而不是 Th9 细胞非富集的细胞，显著增加了激活的 CD8 T 细胞的扩增，这种方式依赖于 IL-9R 的表达。此外，肿瘤中 Th9 细胞的频率与 CD8 TILs 的频率呈正相关。总之，我们证明了 Th9 细胞浸润 CRC 肿瘤，可以通过 PD-1/PD-L1 途径进行调节，并有助于 CD8 T 细胞的扩增。
