Regulatory T Cells Recruited through CCL22/CCR4 Are Selectively Activated in Lymphoid Infiltrates Surrounding Primary Breast Tumors and Lead to an Adverse Clinical Outcome
Regulatory T Cells Recruited through CCL22/CCR4 Are Selectively Activated in Lymphoid Infiltrates Surrounding Primary Breast Tumors and Lead to an Adverse Clinical Outcome
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DOI：
10.1158/0008-5472.can-08-2360
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发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Menetrier-Caux, Christine
中科院分区：
文献类型：
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作者：
Gobert, Michael;Treilleux, Isabelle;Menetrier-Caux, Christine
原发性乳腺肿瘤中FOXP 3的免疫组织化学分析显示，与肿瘤床内存在的肿瘤浸润性调节性T细胞（Ti-Treg）相比，肿瘤周围淋巴浸润内大量的肿瘤浸润性调节性T细胞（Ti-Treg）可预测复发和死亡。体外分析显示，这些肿瘤浸润性FOXP 3（+）T细胞是典型的Treg，基于其CD 4（+）CD 25（高）CD 127（低）FOXP 3（+）表型、其对体外刺激的无反应性状态和其抑制功能。这些Ti-Treg可以通过CCR 4选择性地募集，如（a）选择性血液Treg CCR 4表达和向CCR 4配体的迁移，（B）CCR 4对Ti-Treg的下调，和（c）淋巴浸润中的Ti-Treg与肿瘤内CCL 22表达之间的相关性所示。重要的是，与其他T细胞相反，Ti-Treg选择性地局部活化并原位增殖，显示出T细胞受体接合并表明对肿瘤相关抗原（TAA）的特异性识别。ICOS、Ki 67和DC-LAMP免疫组织化学染色显示，Ti-Treg在淋巴浸润中接近成熟DC-LAMP（+）树突状细胞（DC），但在肿瘤床中不接近，且被激活和增殖。此外，在淋巴浸润中记录了Ti-Treg、CD 3（+）和CD 8（+）T细胞之间的接近。总之，这些结果表明，Treg在淋巴浸润内被选择性募集，并可能通过TAA呈递被成熟DC激活，从而防止效应T细胞活化、免疫逃逸和最终肿瘤进展。这项研究为Treg生理学提供了新的线索，并验证了CCR 4/CCL 22和ICOS作为乳腺肿瘤的治疗靶点，这是一个主要的健康问题。[Cancer Res 2009;69（5）：2000-9]
Immunohistochemical analysis of FOXP3 in primary breast tumors showed that a high number of tumor-infiltrating regulatory T cells (Ti-Treg) within lymphoid infiltrates surrounding the tumor was predictive of relapse and death, in contrast to those present within the tumor bed. Ex vivo analysis showed that these tumor-infiltrating FOXP3(+) T cells are typical Treg based on their CD4(+)CD25(high)CD127(low)FOXP3(+) phenotype, their anergic state on in vitro stimulation, and their suppressive functions. These Ti-Treg could be selectively recruited through CCR4 as illustrated by (a) selective blood Treg CCR4 expression and migration to CCR4 ligands, (b) CCR4 down-regulation on Ti-Treg, and (c) correlation between Ti-Treg in lymphoid infiltrates and intratumoral CCL22 expression. Importantly, in contrast to other T cells, Ti-Treg are selectively activated locally and proliferate in situ, showing T-cell receptor engagement and suggesting specific recognition of tumor-associated antigens (TAA). immunohistochemical stainings for ICOS, Ki67, and DC-LAMP show that Ti-Treg were close to mature DC-LAMP(+) dendritic cells (DC) in lymphoid infiltrates but not in tumor bed and were activated and proliferating. Furthermore, proximity between Ti-Treg, CD3(+), and CD8(+) T cells was documented within lymphoid infiltrates. Altogether, these results show that Treg are selectively recruited within lymphoid infiltrates and activated by mature DC likely through TAA presentation, resulting in the prevention of effector T-cell activation, immune escape, and ultimately tumor progression. This study sheds new light on Treg physiology and validates CCR4/CCL22 and ICOS as therapeutic targets in breast tumors, which represent a major health problem. [Cancer Res 2009;69(5):2000-9]