The role of Tim-3/Galectin-9 pathway in T-cell function and prognosis of patients with human papilloma virus-associated cervical carcinoma
The role of Tim-3/Galectin-9 pathway in T-cell function and prognosis of patients with human papilloma virus-associated cervical carcinoma
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Tim-3/Galectin-9通路在人乳头瘤病毒相关宫颈癌患者T细胞功能及预后中的作用
DOI：
10.1096/fj.202000528rr
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发表时间：
2021-03-01
期刊：
影响因子：
4.8
通讯作者：
Ding, Jianbing
中科院分区：
文献类型：
--
作者：
Chen, Zhifang;Dong, Di;Ding, Jianbing
T 细胞上的 Tim-3 与其配体 Galectin-9 之间的相互作用会负向调节细胞免疫反应。然而，Tim-3/Galectin-9通路在宫颈癌免疫逃避中的作用仍不清楚。本研究旨在探讨Tim-3/Galectin-9信号通路在人乳头瘤病毒（HPV）阳性宫颈癌中的表达、功能和调控。流式细胞术显示，HPV阳性宫颈癌患者T细胞上Tim-3表达量和单核细胞上Galectin-9表达量显着高于宫颈上皮内瘤变和良性子宫肌瘤，HPV阳性宫颈癌患者术后Tim-3+CD4+Th1细胞和Tim-3+CD8+T细胞明显减少。血清TGF-β、IL-10水平与Tim-3+Treg细胞呈正相关，而IFN-γ、IL-2水平与Tim-3+Th1细胞呈负相关。此外，Tim-3 + CD4+ T 细胞与 Galectin-9 + 单核细胞呈正相关。生存曲线分析显示，Tim-3+CD4+T细胞与患者生存呈负相关，且与HPV阳性宫颈癌的FIGO分期、分化程度、淋巴结转移密切相关。体外实验表明，通过阻断Tim-3/Galectin-9通路，T细胞的增殖及其表达IFN-γ、IL-2、穿孔素和颗粒酶B的能力显着恢复。总之，HPV阳性宫颈癌患者体内高水平的Tim-3和Galectin-9通过促进Treg细胞抑制Th1和CD8+ T细胞的细胞毒功能而在疾病进展中发挥作用。 Tim-3/Galectin-9可能作为HPV阳性宫颈癌患者的新免疫治疗靶点。
The interaction between Tim-3 on T cell and its ligand, Galectin-9, negatively regulates cellular immune responses. However, the role of Tim-3/Galectin-9 pathway in the immune evasion of cervical cancer remains unknown. This study is to investigate the expression, function, and regulation of Tim-3/Galectin-9 signaling pathway in human papilloma virus (HPV) positive cervical cancer. Flow cytometry showed that Tim-3 expression on T cell and Galectin-9 expression on monocytes in HPV positive cervical cancer patients were significantly higher compared to cervical intraepithelial neoplasia and benign uterine fibroids Tim-3 + CD4+ Th1 cells and Tim-3 + CD8+ T cells in HPV positive cervical cancer patients were significantly reduced after surgery. Serum TGF-beta and IL-10 levels were positively correlated with Tim-3 + Treg cells, while IFN-gamma and IL-2 were negatively correlated with Tim-3 + Th1 cells. Additionally, Tim-3 + CD4+ T cells were positively correlated with Galectin-9 + monocytes. Survival curve analysis showed that Tim-3 + CD4+ T cells were negatively correlated with patient survival, and closely related to FIGO stage, degree of differentiation, and lymph node metastasis of HPV positive cervical cancer. In vitro experiments showed that by blocking the Tim-3/Galectin-9 pathway, the proliferation of T cells and their ability to express IFN-gamma, IL-2, perforin, and granzyme B was significantly restored. In conclusion, high levels of Tim-3 and Galectin-9 in HPV positive cervical cancer patients play roles in the progression of disease by promoting Treg cells to inhibit the cytotoxic function of Th1 and CD8+ T cells. Tim-3/Galectin-9 may serve as a new immunotherapy target for patients with HPV positive cervical cancer.