Blocking the recruitment of naive CD4(+) T cells reverses immunosuppression in breast cancer.
Blocking the recruitment of naive CD4(+) T cells reverses immunosuppression in breast cancer.
复制标题
阻断初始 CD4( ) T 细胞的募集可逆转乳腺癌的免疫抑制
DOI：
10.1038/cr.2017.34
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发表时间：
2017-04
期刊：
影响因子：
44.1
通讯作者：
Song E
中科院分区：
文献类型：
--
作者：
Su S;Liao J;Liu J;Huang D;He C;Chen F;Yang L;Wu W;Chen J;Lin L;Zeng Y;Ouyang N;Cui X;Yao H;Su F;Huang JD;Lieberman J;Liu Q;Song E
The 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.
