Volume 27, No 4, Apr 2017

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 27 Issue 4, April 2017: 461-482   |  Open Access

ORIGINAL ARTICLES

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

Shicheng Su^1,2, Jianyou Liao¹, Jiang Liu^1,2, Di Huang^1,2, Chonghua He^1,2, Fei Chen^1,2, LinBing Yang^1,2, Wei Wu^1,2, Jianing Chen^1,2, Ling Lin³, Yunjie Zeng⁴, Nengtai Ouyang⁴, Xiuying Cui^1,2, Herui Yao^1,2, Fengxi Su^1,2, Jian-dong Huang⁵, Judy Lieberman⁶, Qiang Liu^1,2 and Erwei Song^1,2

¹Guangdong 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
²Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
³Department of Internal Medicine, The First Affiliated Hospital, Shantou University Medical College, Shantou, Guangdong 515041, China
⁴Department of Pathology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China
⁵Department of Biochemistry, the University of Hong Kong, Hong Kong, SAR, China
⁶Department of Pediatrics, Program in Cellular and Molecular Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA Correspondence: Erwei Song, E-mail: songew@mail.sysu.edu.cn; Qiang Liu, E-mail: victorlq@hotmail.com; Judy Lieberman,(judy.lieberman@childrens.harvard.edu)

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.

10.1038/cr.2017.34

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