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

作　　者：Shicheng Su Jianyou Liao Jiang Liu Di Huang Chonghua He Fei Chen LinBing Yang Wei Wu Jianing Chen Ling Lin Yunjie Zeng Nengtai Ouyang Xiuying Cui Herui Yao Fengxi Su Jian-dong Huang Judy Lieberman Qiang Liu Erwei Song 

机构地区：[1]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, SunYat-Sen Memorial Hospital Sun Yat-Sen University, Guangzhou, Guangdong 510120, China [2]Breast Tumor Center, Sun Yat-SenMemorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510120, China [3]Department of Internal Medicine, The FirstAffiliated 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 Uni-versity of Hong Kong, Hong Kong, SAR, China [6]Department of Pediatrics, Program in Cellular and Molecular Medicine, BostonChildren's Hospital Harvard Medical School Boston, MA, USA

出　　处：《Cell Research》2017年第4期461-482,共22页细胞研究（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China （81472468, 81672614, 81622036, 81490750, 81230060, 81442009, 81472467, 81272894, 81372816 and 81372819）, the Science Foundation of Guangdong Province （2016A030306023, 2014A030313094, $2012030006287, 2014A030313175）, the National Basic Research Program of China （973 Projects; SQ2015CB050449）, Guangzhou Science Technology and Innovation Commission （201508020008, 201508020249）, Guangdong Science and Technology Department （2015B050501004）, Translational Medicine Public Plat- form of Guangdong Province （4202037）, Guangdong Depart- ment of Science ＆ Technology Translational Medicine Center （2011A080300002）, Sun Yat-Sen University （16ykpy07）, Breast Cancer Alliance Exceptional Project Grant and US National Cancer Institute RO1 CA211694.

摘　　要：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 infil- trate 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.

关 键 词：naive CD4＋ T cells breast cancer TREGS CCL 18 tumor immunosuppression 

分 类 号：Q2[生物学—细胞生物学] S858.292[农业科学—临床兽医学]