CD30L/CD30 signaling regulates the formation of the tumor immune microenvironment and inhibits intestinal tumor development of colitis-associated colon cancer in mice
CD30L/CD30 signaling regulates the formation of the tumor immune microenvironment and inhibits intestinal tumor development of colitis-associated colon cancer in mice
复制标题
CD30L/CD30信号调节肿瘤免疫微环境的形成并抑制小鼠结肠炎相关结肠癌的肠道肿瘤发展
DOI：
10.1016/j.intimp.2020.106531
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发表时间：
2020
影响因子：
5.6
通讯作者：
Sun Xun
中科院分区：
文献类型：
--
作者：
Wang Xiao;Gao Yaxian;Zhang Xiaoqing;Wang Xiaonan;Wang Biao;Meng Xin;Yoshikai Yasunobu;Wang Yuanyuan;Sun Xun
炎症性肠病是结肠炎相关结肠癌（CAC）的主要原因之一。因此，有必要从慢性炎症与肿瘤发生发展的关系出发，探索新的治疗方法来预防结肠癌。以往关于CD 30 L/CD 30与肿瘤相关性的研究多局限于淋巴系或同种肿瘤，而关于CD 30 L/CD 30信号转导在CAC发病机制中的作用的报道较少。本研究采用CD 30 LKO小鼠建立AOM/DSS诱导的CAC模型，探讨CD 30 L/CD 30信号转导在肠道肿瘤发生发展过程中对肠道肿瘤免疫微环境（TIME）形成的影响。我们的研究结果表明，CD 30 L缺乏促进骨髓源性抑制细胞（MDSC）的积累，增加MDSC和肿瘤相关巨噬细胞（TAMs）上PD-L1的表达，并增加CAC小鼠肠粘膜中各种炎症和免疫抑制因子的分泌。此外，CD 30 L基因缺失可选择性上调CD 4+和CD 8 +T细胞PD-1表达，抑制其活化、分化和效应细胞因子的分泌，从而减弱TEM（CD 44 + CD 62 L-）细胞介导的抗肿瘤免疫应答。因此，我们的数据表明，CD 30 L/CD 30信号转导可能是一个潜在的候选目标，免疫治疗CAC。
Inflammatory bowel disease is one of the major causes of colitis-associated colon cancer (CAC). Therefore, it is necessary to explore new therapies to prevent colon cancer (CRC) in view of the relationship between chronic inflammation and tumor development. Previous studies on the correlation between CD30L/CD30 and cancer were mostly limited to lymphoid or homogenous tumors, while there have been only a few reports on the role of CD30L/CD30 signal transduction in the pathogenesis of CAC. In this study, we established an AOM/DSS-induced CAC model with CD30LKO mice to explore the effect of CD30L/CD30 signal transduction on the formation of the intestinal tumor immune microenvironment (TIME) during the development of intestinal tumors. Our results revealed that CD30L deficiency promoted the accumulation of myeloid derived suppressor cells (MDSCs), increased the expression of PD-L1 on MDSCs and tumor associated macrophages (TAMs), and enhanced the secretion of various inflammatory and immunosuppressive factors in the intestinal mucosa of CAC mice. Furthermore, CD30L gene deletion could selectively promote the upregulation of PD-1 expression on CD4+and CD8+T cells and inhibit their activation, differentiation and secretion of effector cytokines, which led to an attenuation of antitumor immune responses mediated by TEM(CD44+CD62L-) cells. Thus, our data suggest that CD30L/CD30 signaling might be a potential candidate target for immunological therapy in CAC.