CCL17 acts as an antitumor chemokine in micromilieu-driven immune skewing.
CCL17 acts as an antitumor chemokine in micromilieu-driven immune skewing.
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DOI：
10.1016/j.intimp.2023.110078
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发表时间：
2023-03
影响因子：
5.6
通讯作者：
Ya-dan Li;Haixia Cao;Zhongxing Jiang;Ketai Yan;Jianxiang Shi;Shuya Wang;Fang Wang;Weiqiong Wang;Xue Li;Na Sun;Liu Liu-Liu;Li Chen;Yali Chen;Rongqun Guo;Yongping Song
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作者：
Ya-dan Li;Haixia Cao;Zhongxing Jiang;Ketai Yan;Jianxiang Shi;Shuya Wang;Fang Wang;Weiqiong Wang;Xue Li;Na Sun;Liu Liu-Liu;Li Chen;Yali Chen;Rongqun Guo;Yongping Song
背景趋化因子在肿瘤局部免疫反应中起重要作用。CCL 17（胸腺和活化调节趋化因子，TARC）和CCL 22（巨噬细胞衍生趋化因子，MDC）可以吸引涉及癌症免疫景观的CCR 4携带细胞。然而，它们在肿瘤中的直接作用和功能状态在很大程度上仍然不清楚。MethodsWe分析了淋巴瘤相关的scRNA-seq和bulk RNA-seq数据集，并确定了CCL 17/CCL 22-CCR 4轴作为肿瘤微环境的独特参与者。然后，我们编辑A20淋巴瘤细胞系以表达CCL 17和CCL 22，并使用三种小鼠模型（Balb/C小鼠、裸小鼠和NSG小鼠）评估它们的功能。此外，我们回顾性检查CCL 17/CCL 22-CCR 4轴和癌症patients.ResultsThe活跃的CCL 17/CCL 22-CCR 4轴的生存率之间的关系是霍奇金淋巴瘤微环境的一个显着特点。CCR 4在免疫细胞中广泛表达，但高度存在于NK、NKT和Treg细胞的表面。Balb/C小鼠的肿瘤模型表明，CCL 17作为一种由活化的T细胞应答介导的抗肿瘤趋化因子。此外，裸鼠肿瘤模型显示，CCL 17募集NK细胞以抑制淋巴瘤生长，并增强NK-cDC 1相互作用以抵抗IL 4 i 1介导的免疫抑制。有趣的是，CCL 17介导的抗肿瘤免疫应答依赖于淋巴系，而不是主要的髓系。此外，我们发现CCL 17/CCL 22-CCR 4轴不能被视为在大多数癌症类型的预后不良的生物标志物从TCGA database.ConclusionWe提供了直接的证据，CCL 17介导的抗肿瘤功能的募集的常规T细胞，NKT细胞，NK细胞。靶基因CCL 17、CCL 22和CCR 4表达的临床生存结局也证实了CCL 17/CCL 22-CCR 4轴不是预后不良的标志。
BackgroundChemokines are critical players in the local immune responses to tumors. CCL17 (thymus and activation-regulated chemokine, TARC) and CCL22 (macrophage-derived chemokine, MDC) can attract CCR4-bearing cells involving the immune landscape of cancer. However, their direct roles and functional states in tumors remain largely unclear.MethodsWe analyzed the lymphoma-related scRNA-seq and bulk RNA-seq datasets and identified the CCL17/CCL22-CCR4 axis as the unique participant of the tumor microenvironment. Then we edited the A20 lymphoma cell line to express CCL17 and CCL22 and assessed their function using three mouse models (Balb/C mouse, Nude mouse, and NSG mouse). In addition, we retrospectively checked the relationship between the CCL17/CCL22-CCR4 axis and the survival rates of cancer patients.ResultsThe active CCL17/CCL22-CCR4 axis is a distinctive feature of the Hodgkin lymphoma microenvironment. CCR4 is widely expressed in immune cells but highly exists on the surface of NK, NKT, and Treg cells. The tumor model of Balb/C mice showed that CCL17 acts as an anti-tumor chemokine mediated by activated T cell response. In addition, the tumor model of Nude mice showed that CCL17 recruits NK cells for inhibiting lymphoma growth and enhances the NK-cDC1 interaction for resisting IL4i1-mediated immunosuppression. Interestingly, CCL17-mediated antitumor immune responses depend on lymphoid lineages but not mainly myeloid ones. Furthermore, we found CCL17/CCL22-CCR4 axis cannot be regarded as biomarkers of poor prognosis in most cancer types from the TCGA database.ConclusionWe provided direct evidence of antitumor functions of CCL17 mediated by the recruitment of conventional T cells, NKT cells, and NK cells. Clinical survival outcomes of target gene (CCL17,CCL22, andCCR4) expression also identified that CCL17/CCL22-CCR4 axis is not a marker of poor prognosis.