Tumor Microenvironments Direct the Recruitment and Expansion of Human Th17 Cells
Tumor Microenvironments Direct the Recruitment and Expansion of Human Th17 Cells
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DOI：
10.4049/jimmunol.0902813
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发表时间：
2010-02-01
影响因子：
4.4
通讯作者：
Peng, Guangyong
中科院分区：
文献类型：
--
作者：
Su, Xinming;Ye, Jian;Peng, Guangyong
虽然Th 17细胞在许多炎症和自身免疫性疾病的发病机制中起着关键作用，但它们在肿瘤浸润淋巴细胞（TIL）中的流行率和在人类肿瘤免疫中的功能在很大程度上仍然未知。我们最近证明了卵巢癌患者的TIL中Th 17细胞的比例很高，但这些Th 17细胞在肿瘤微环境中积累的机制仍不清楚。在这项研究中，我们进一步显示了从黑色素瘤和乳腺癌和结肠癌中获得的TIL中Th 17细胞群的升高，表明肿瘤浸润性CD 4（+）Th 17细胞的发展可能是癌症患者的普遍特征。然后，我们证明了肿瘤微环境RANTES和MCP-1分泌的肿瘤细胞和肿瘤来源的成纤维细胞介导的募集Th 17细胞。除了它们的募集，我们发现肿瘤细胞和肿瘤来源的成纤维细胞产生促炎细胞因子环境，以及提供细胞-细胞接触接合，促进Th 17细胞的产生和扩增。我们还发现，炎症TLR和核苷酸寡聚化结合结构域2信号促进肿瘤细胞和肿瘤源性成纤维细胞诱导的Th 17细胞的吸引和产生。这些结果确定了Th 17细胞作为人类TIL的重要组成部分，展示了参与肿瘤微环境中Th 17细胞募集和调节的机制，并为开发新型癌症免疫方法提供了新的见解。免疫学杂志，2010，184：1630-1641.
Although Th17 cells play critical roles in the pathogenesis of many inflammatory and autoimmune diseases, their prevalence among tumor-infiltrating lymphocytes (TILs) and function in human tumor immunity remains largely unknown. We have recently demonstrated high percentages of Th17 cells in TILs from ovarian cancer patients, but the mechanisms of accumulation of these Th17 cells in the tumor microenvironment are still unclear. In this study, we further showed elevated Th17 cell populations in the TILs obtained from melanoma and breast and colon cancers, suggesting that development of tumor-infiltrating CD4(+) Th17 cells may be a general feature in cancer patients. We then demonstrated that tumor microenvironmental RANTES and MCP-1 secreted by tumor cells and tumor-derived fibroblasts mediate the recruitment of Th17 cells. In addition to their recruitment, we found that tumor cells and tumor-derived fibroblasts produce a proinflammatory cytokine milieu as well as provide cell-cell contact engagement that facilitates the generation and expansion of Th17 cells. We also showed that inflammatory TLR and nucleotide oligomerization binding domain 2 signaling promote the attraction and generation of Th17 cells induced by tumor cells and tumor-derived fibroblasts. These results identify Th17 cells as an important component of human TILs, demonstrate mechanisms involved in the recruitment and regulation of Th17 cells in tumor microenvironments, and provide new insights relevant for the development of novel cancer immunotherapeutic approaches. The Journal of Immunology, 2010,184: 1630-1641.