Specific recruitment of γδ regulatory T cells in human breast cancer.
Specific recruitment of γδ regulatory T cells in human breast cancer.
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DOI：
10.1158/0008-5472.can-13-0348
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发表时间：
2013-10-15
期刊：
影响因子：
11.2
通讯作者：
Peng G
中科院分区：
文献类型：
--
作者：
Ye J;Ma C;Wang F;Hsueh EC;Toth K;Huang Y;Mo W;Liu S;Han B;Varvares MA;Hoft DF;Peng G
了解不同亚型肿瘤浸润淋巴细胞（til）在免疫抑制肿瘤微环境中的作用对改善癌症治疗至关重要。肿瘤浸润淋巴细胞（til）中富集的γδ1 T细胞群抑制乳腺癌中T细胞反应和树突状细胞成熟，其存在与临床结果呈负相关。然而，解释这类T调节细胞（γδ Treg）在乳腺癌患者中增加的机制尚未阐明。在这项研究中，我们发现乳腺癌细胞分泌的IP-10吸引了γδ Treg细胞。利用针对乳腺癌细胞分泌的趋化因子的中和抗体，我们发现IP-10是导致γδ Treg细胞向乳腺癌细胞迁移的唯一功能趋化因子。在人源化NSG小鼠模型中，活细胞成像系统显示，人乳腺癌细胞吸引γδ Treg细胞。体内IP-10中和抑制γδ Treg细胞向乳腺肿瘤部位的迁移和运输，增强肿瘤特异性T细胞介导的肿瘤免疫。总之，我们的研究显示了γδ Treg如何在乳腺肿瘤中积累，为其免疫靶向缓解肿瘤微环境中的免疫抑制提供了理论依据。
Understanding the role of different subtypes of tumor-infiltrating lymphocytes (TILs) in the immunosuppressive tumor microenvironment is essential to improving cancer treatment. Enriched γδ1 T cell populations in tumor-infiltrating lymphocytes (TILs) suppress T cell responses and dendritic cell maturation in breast cancer, where their presence is correlated negatively with clinical outcomes. However, mechanism(s) that explain the increase in this class of T regulatory cells (γδ Treg) in breast cancer patients have yet to be elucidated. In this study, we showed that IP-10 secreted by breast cancer cells attracted γδ Treg cells. Using neutralizing antibodies against chemokines secreted by breast cancer cells, we found that IP-10 was the only functional chemokine that causes γδ Treg cells to migrate toward breast cancer cells. In a humanized NSG mouse model, human breast cancer cells attracted γδ Treg cells as revealed by a live cell imaging system. IP-10 neutralization in vivo inhibited migration and trafficking of γδ Treg cells into breast tumor sites, enhancing tumor immunity mediated by tumor-specific T cells. Together, our studies show how γδ Treg accumulate in breast tumors, providing a rationale for their immunological targeting to relieve immunosuppression in the tumor microenvironment.