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Cell Res. 2017 Apr;27(4):461-482. doi: 10.1038/cr.2017.34. Epub 2017 Mar 14.

Blocking the recruitment of naive CD4+ T cells reverses immunosuppression in breast cancer.

Su S1,2, Liao J1, Liu J1,2, Huang D1,2, He C1,2, Chen F1,2, Yang L1,2, Wu W1,2, Chen J1,2, Lin L3, Zeng Y4, Ouyang N4, Cui X1,2, Yao H1,2, Su F1,2, Huang JD5, Lieberman J6, Liu Q1,2, Song E1,2.

Author information

1
Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China.
2
Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China.
3
Department of Internal Medicine, The First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong 515041, China.
4
Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China.
5
Department of Biochemistry, the University of Hong Kong, Hong Kong, SAR, China.
6
Department of Pediatrics, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.

Abstract

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.

PMID:
28290464
PMCID:
PMC5385617
DOI:
10.1038/cr.2017.34
[Indexed for MEDLINE]
Free PMC Article

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