CD4+ follicular helper T cell infiltration predicts breast cancer survival
CD4+ follicular helper T cell infiltration predicts breast cancer survival
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DOI：
10.1172/jci67428
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发表时间：
2013-07-01
影响因子：
15.9
通讯作者：
Willard-Gallo, Karen
中科院分区：
文献类型：
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作者：
Gu-Trantien, Chunyan;Loi, Sherene;Willard-Gallo, Karen
CD 4（+）T细胞是免疫反应的关键调节因子，但其在人类乳腺癌中的功能作用相对未知。本研究的目的是使用有限的离体操作产生浸润乳腺肿瘤的CD 4（+）T细胞的图像，以更好地理解与患者预后相关的体内差异。我们对从未经治疗的浸润性原发性肿瘤中分离的浸润性CD 4（+）T细胞进行了全面的分子分析，发现浸润性T细胞亚群包括滤泡辅助性T（Tfh）细胞，这在以前的实体瘤中没有发现，以及Th 1，Th 2和Th 17效应记忆细胞和Tfh。T细胞信号通路改变包括活化和抑制的混合物，其特征在于限制细胞因子/趋化因子的产生，其反向降低淋巴浸润水平，并且可以在用原代肿瘤上清液处理的活化供体CD 4（+）T细胞中再现。广泛浸润与最小浸润肿瘤的比较显示，产生CXCL 13的CD 4（+）Tfh细胞区分广泛的免疫浸润，主要位于三级淋巴结构生发中心。一个8基因的Tfh签名，标志着有组织的抗肿瘤免疫，有力地预测生存或术前化疗反应。我们对乳腺癌中CD 4（+）Tfh细胞的鉴定表明，它们是一种重要的免疫因子，其在肿瘤中的存在是一个预后因素。
CD4(+) T cells are critical regulators of immune responses, but their functional role in human breast cancer is relatively unknown. The goal of this study was to produce an image of CD4(+) T cells infiltrating breast tumors using limited ex vivo manipulation to better understand the in vivo differences associated with patient prognosis. We performed comprehensive molecular profiling of infiltrating CD4(+) T cells isolated from untreated invasive primary tumors and found that the infiltrating T cell subpopulations included follicular helper T (Tfh) cells, which have not previously been found in solid tumors, as well as Th1, Th2, and Th17 effector memory cells and Tregs. T cell signaling pathway alterations included a mixture of activation and suppression characterized by restricted cytokine/chemokine production, which inversely paralleled lymphoid infiltration levels and could be reproduced in activated donor CD4(+) T cells treated with primary tumor supernatant. A comparison of extensively versus minimally infiltrated tumors showed that CXCL13-producing CD4(+) Tfh cells distinguish extensive immune infiltrates, principally located in tertiary lymphoid structure germinal centers. An 8-gene Tfh signature, signifying organized antitumor immunity, robustly predicted survival or preoperative response to chemotherapy. Our identification of CD4(+) Tfh cells in breast cancer suggests that they are an important immune element whose presence in the tumor is a prognostic factor.