Activated CD69+ T Cells Foster Immune Privilege by Regulating IDO Expression in Tumor-Associated Macrophages
Activated CD69+ T Cells Foster Immune Privilege by Regulating IDO Expression in Tumor-Associated Macrophages
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DOI：
10.4049/jimmunol.1100164
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发表时间：
2012-02
期刊：
影响因子：
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通讯作者：
Qiyi Zhao;D. Kuang;Yan Wu;Xiao Xiao-Xiao;Xue-feng Li;Tuan-jie Li;Limin Zheng
中科院分区：
文献类型：
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作者：
Qiyi Zhao;D. Kuang;Yan Wu;Xiao Xiao-Xiao;Xue-feng Li;Tuan-jie Li;Limin Zheng
大量证据表明，免疫激活在基质中可以重新路由在肿瘤促进方向。CD 69是由慢性炎症部位的早期活化的白细胞表达的免疫调节分子，并且已经发现CD 69 + T细胞促进人类肿瘤进展。在这项研究中，我们表明，在遇到自体CD 69 + T细胞时，肿瘤巨噬细胞（MΦ）获得了在癌巢中产生大量IDO蛋白的能力。从肝细胞癌组织中分离的T细胞表达的CD 69分子显著多于配对的循环和非肿瘤浸润T细胞;这些肿瘤来源的CD 69 + T细胞可以在单核细胞中诱导相当大的IDO。有趣的是，从肝细胞癌组织中分离的或通过体外培养产生的肿瘤相关单核细胞/MΦ有效地激活循环T细胞以表达CD 69。来源于肿瘤MΦs的IL-12是早期T细胞活化和随后的IDO表达所需的。此外，我们发现来自IDO+ MΦs的条件培养基在体外有效地抑制T细胞应答，这种作用可以通过添加外源性IDO底物色氨酸或通过用IDO抑制剂1-甲基-DL-色氨酸预处理MΦs来逆转。这些数据揭示了不同类型的免疫细胞之间的微调协同作用，以抵消肿瘤微环境中的T细胞反应。这种免疫耐受的主动诱导应被考虑用于有效的基于免疫的抗癌疗法的合理设计。
Substantial evidence indicates that immune activation at stroma can be rerouted in a tumor-promoting direction. CD69 is an immunoregulatory molecule expressed by early-activated leukocytes at sites of chronic inflammation, and CD69+ T cells have been found to promote human tumor progression. In this study, we showed that, upon encountering autologous CD69+ T cells, tumor macrophages (MΦs) acquired the ability to produce much greater amounts of IDO protein in cancer nests. The T cells isolated from the hepatocellular carcinoma tissues expressed significantly more CD69 molecules than did those on paired circulating and nontumor-infiltrating T cells; these tumor-derived CD69+ T cells could induce considerable IDO in monocytes. Interestingly, the tumor-associated monocytes/MΦs isolated from hepatocellular carcinoma tissues or generated by in vitro culture effectively activated circulating T cells to express CD69. IL-12 derived from tumor MΦs was required for early T cell activation and subsequent IDO expression. Moreover, we found that conditioned medium from IDO+ MΦs effectively suppressed T cell responses in vitro, an effect that could be reversed by adding extrinsic IDO substrate tryptophan or by pretreating MΦs with an IDO inhibitor 1-methyl-DL-tryptophan. These data revealed a fine-tuned collaborative action between different types of immune cells to counteract T cell responses in tumor microenvironment. Such an active induction of immune tolerance should be considered for the rational design of effective immune-based anticancer therapies.