Cancer Res:CXCR3+调节性T细胞参与卵巢肿瘤免疫抑制

7月12日，Cancer Res杂志报道一类CXCR3+调节性T细胞参与卵巢肿瘤的免疫抑制，这或许成为肿瘤免疫治疗的一个新的靶点。

抗肿瘤的I型T细胞反应，涉及IFN-γ的产生是控制癌症的关键，但这种反应的效率受多种免疫抑制机制的限制。这些抑制机制可促进肿瘤免疫逃逸。其中一项免疫抑制机制涉及FOXP3+ 调节性T细胞（Treg）的积累。这类抑制性T细胞可防止过度免疫反应造成的组织破坏。

最近的研究显示，FOXP3 +调节性T细胞包括不同亚群，分别发挥不同的功能。特别是CXCR3+ Treg细胞，已被证明特异性地控制体内的I型T细胞反应。本研究发现，CXCR3+ Treg细胞高度富集于人类卵巢癌，特别是在实体肿瘤中，它们是Treg细胞的主体。

体外实验中，肿瘤相关CXCR3+ Treg细胞共表达T-bet，但不分泌γ-干扰素，也不抑制细胞增殖和T效应细胞的γ-干扰素分泌。此外，它们共表达Helios （Helios是人类胸腺衍生FOXP3 +调节性T细胞的标记），表明它们从天然调节性T细胞起源。最后，科学家证实CXCR3+调节性T细胞在肿瘤部位的比例与CXCR3+T效应细胞直接相关，与CXCR3的配体表达一致。总之，本研究结果支持这一概念，天然CXCR3+/T-bet+调节性T细胞选择性积聚在卵巢肿瘤组织中，控制I型T细胞反应，导致对有效抗肿瘤免疫的抑制。

doi:10.1016/j.cell.2011.10.017
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CXCR3+ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity

Nassima Redjimi1,Caroline Raffin1,Isabelle Raimbaud1,Pascale Pignon1,Junko Matsuzaki2,Kunle Odunsi2,Danila Valmori1,*, andMaha Ayyoub

Anti-tumor Type I T cell responses involving IFN-γ production are critical to control cancer, but the efficacy of this response is limited by a variety of immunsuppressive mechanisms that promote tumoral immune escape. One critical mechanism involves the accumulation of FOXP3+ T regulatory cells (Treg), a class of suppressive T cells that prevent excessive tissue destruction caused by unchecked immune responses. Recent studies have revealed that FOXP3+ Treg include distinct subsets specifically controlling over the corresponding effector subset. In particular, CXCR3+ Treg have been described as a subset specialized in the control of type I T cell responses in vivo. Here we show that CXCR3+ Treg are highly enriched in human ovarian carcinomas, particularly in solid tumor masses, where they represent the majority of Treg. Tumor-associated CXCR3+ Treg co-express T-bet but do not secrete IFN-γ ex vivo and suppress proliferation and IFN-γ secretion of T effectors. In addition, they co-express Helios, suggesting that they originate from natural Treg. Finally, we show that the proportion of CXCR3+ Treg at tumor sites is directly correlated with that of CXCR3+ T effectors, consistent with expression of CXCR3 ligands. Together, our findings support the concept that natural CXCR3+ T-bet+ Treg selectively accumulate in ovarian tumors to control type I T cell responses, resulting in the collateral limitation of efficient anti-tumor immunity.