ICOS-Ligand Expression on Plasmacytoid Dendritic Cells Supports Breast Cancer Progression by Promoting the Accumulation of Immunosuppressive CD4+ T Cells
ICOS-Ligand Expression on Plasmacytoid Dendritic Cells Supports Breast Cancer Progression by Promoting the Accumulation of Immunosuppressive CD4+ T Cells
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DOI：
10.1158/0008-5472.can-12-2409
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发表时间：
2012-12-01
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：
Faget, Julien;Bendriss-Vermare, Nathalie;Menetrier-Caux, Christine
人类乳腺肿瘤被记忆性 CD4+ T 细胞以及数量增加的调节性 T 细胞 (Treg) 和浆细胞样树突状细胞 (pDC) 浸润，这些细胞促进免疫逃逸并与不良预后相关。在这里，我们报道了诱导型共刺激分子（ICOS），一种 CTLA4/PD1/CD28 家族的 T 细胞共刺激分子，主要由原发性乳腺肿瘤中的肿瘤相关 Treg 表达。这些 ICOS+ Treg 中的很大一部分是 Ki67(+)，并且发现这种明显的增殖扩张依赖于与肿瘤相关的 pDC 的相互作用。事实上，肿瘤相关 Treg 在 pDC 存在下高度扩增，但在 CD3/CD28 信号下无法增殖。体外实验表明，添加中和性抗ICOS抗体可阻断pDC诱导的Treg扩增和记忆CD4+T细胞分泌白细胞介素10，从而确立了ICOS在此过程中的关键作用。乳腺癌临床标本中 ICOS+ 细胞的存在与不良预后相关，支持了这些发现。总之，我们的结果强调了乳腺肿瘤中 Treg 和 pDC 之间的重要关系，并表明 ICOS/ICOS-L 相互作用是肿瘤相关记忆 CD4(+) T 细胞免疫抑制的核心事件。这些发现有力地证明了抗体介导的 ICOS 阻断是纠正免疫逃逸和促进乳腺癌治疗反应的强大临床策略。癌症研究； 72（23）； 6130-41。 (C) 2012 年 AACR。
Human breast tumors are infiltrated by memory CD4(+) T cells along with increased numbers of regulatory T cells (Treg) and plasmacytoid dendritic cells (pDC) that facilitate immune escape and correlate with poor prognosis. Here, we report that inducible costimulatory molecule (ICOS), a T cell costimulatory molecule of the CTLA4/PD1/CD28 family, is expressed mostly by tumor-associated Treg in primary breast tumors. A large proportion of these ICOS+ Treg were Ki67(+) and this evident proliferative expansion was found to rely on interactions with tumor-associated pDC. Indeed, tumor-associated Treg highly expanded in presence of pDC but failed to proliferate under CD3/CD28 signal. In vitro experiments revealed that the addition of a neutralizing anti-ICOS antibody blocked pDC-induced Treg expansion and interleukin-10 secretion by memory CD4(+) T cells, establishing a pivotal role for ICOS in this process. Supporting these findings, the presence of ICOS+ cells in clinical specimens of breast cancer correlated with a poor prognosis. Together, our results highlight an important relationship between Treg and pDC in breast tumors, and show that ICOS/ICOS-L interaction is a central event in immunosuppression of tumor-associated memory CD4(+) T cells. These findings strongly rationalize antibody-mediated ICOS blockade as a powerful clinical strategy to correct immune escape and promote therapeutic responses in breast cancer. Cancer Res; 72(23); 6130-41. (C) 2012 AACR.