Su, ShichengLiao, JianyouLiu, JiangHuang, DiHe, ChonghuaChen, FeiYang, LinBingWu, WeiChen, JianingLin, LingZeng, YunjieOuyang, NengtaiCui, XiuyingYao, HeruiSu, FengxiHuang, Jian-dongLieberman, JudyLiu, QiangSong, Erwei2017-05-012017Su, S., J. Liao, J. Liu, D. Huang, C. He, F. Chen, L. Yang, et al. 2017. “Blocking the recruitment of naive CD4+ T cells reverses immunosuppression in breast cancer.” Cell Research 27 (4): 461-482. doi:10.1038/cr.2017.34. http://dx.doi.org/10.1038/cr.2017.34.http://nrs.harvard.edu/urn-3:HUL.InstRepos:32630628The origin of tumor-infiltrating Tregs, critical mediators of tumor immunosuppression, is unclear. Here, we show that tumor-infiltrating naive CD4+ T cells and Tregs in human breast cancer have overlapping TCR repertoires, while hardly overlap with circulating Tregs, suggesting that intratumoral Tregs mainly develop from naive T cells in situ rather than from recruited Tregs. Furthermore, the abundance of naive CD4+ T cells and Tregs is closely correlated, both indicating poor prognosis for breast cancer patients. Naive CD4+ T cells adhere to tumor slices in proportion to the abundance of CCL18-producing macrophages. Moreover, adoptively transferred human naive CD4+ T cells infiltrate human breast cancer orthotopic xenografts in a CCL18-dependent manner. In human breast cancer xenografts in humanized mice, blocking the recruitment of naive CD4+ T cells into tumor by knocking down the expression of PITPNM3, a CCL18 receptor, significantly reduces intratumoral Tregs and inhibits tumor progression. These findings suggest that breast tumor-infiltrating Tregs arise from chemotaxis of circulating naive CD4+ T cells that differentiate into Tregs in situ. Inhibiting naive CD4+ T cell recruitment into tumors by interfering with PITPNM3 recognition of CCL18 may be an attractive strategy for anticancer immunotherapy.en-USnaive CD4breast cancerTregsCCL18tumor immunosuppressionJournal Article2017-05-0110.1038/cr.2017.34