IL6 Modulates the Immune Status of the Tumor Microenvironment to Facilitate Metastatic Colonization of Colorectal Cancer Cells
IL6 Modulates the Immune Status of the Tumor Microenvironment to Facilitate Metastatic Colonization of Colorectal Cancer Cells
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DOI：
10.1158/2326-6066.cir-18-0766
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发表时间：
2019-12-01
影响因子：
10.1
通讯作者：
Taketomi, Akinobu
中科院分区：
文献类型：
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作者：
Toyoshima, Yujiro;Kitamura, Hidemitsu;Taketomi, Akinobu
目前尚不清楚结直肠癌肝转移与宿主免疫状态的关系。在这项研究中，我们发现IL 6，一种在荷瘤状态下产生的促炎细胞因子，促进了结肠癌细胞的转移定植，并与功能失调的抗肿瘤免疫相关。在IL 6缺陷小鼠中，CT 26细胞在肝脏中的转移性定殖减少，并且体内CD 8（+）T细胞的抗肿瘤效应功能以及CD 11 c（+）树突状细胞的IL 12产生增强。IL 6缺陷小鼠表现出增强的IFN-AR 1介导的I型干扰素信号传导，其上调CT 26细胞上的PD-L1和MHC I类表达。体内注射抗PD-L1可有效抑制IL 6（-/-）小鼠中CT 26细胞的转移性定植，但在IL 6（+/+）小鼠中则无此作用。最后，我们证实，原发性肿瘤中IL 6表达较低的结直肠癌患者的无病生存期延长。这些结果表明，IL 6可能是一个有前途的目标，通过改善宿主免疫治疗转移的结直肠癌。
It is unknown as to how liver metastases are correlated with host immune status in colorectal cancer. In this study, we found that IL6, a proinflammatory cytokine produced in tumor-bearing states, promoted the metastatic colonization of colon cancer cells in association with dysfunctional antitumor immunity. In IL6-deficient mice, metastatic colonization of CT26 cells in the liver was reduced, and the antitumor effector function of CD8(+) T cells, as well as IL12 production by CD11c(+) dendritic cells, were augmented in vivo. IL6-deficient mice exhibited enhanced IFN-AR1-mediated type I interferon signaling, which upregulated PD-L1 and MHC class I expression on CT26 cells. In vivo injection of anti-PD-L1 effectively suppressed the metastatic colonization of CT26 cells in Il6(-/-) but not in Il6(+/+) mice. Finally, we confirmed that colorectal cancer patients with low IL6 expression in their primary tumors showed prolonged disease-free survival. These findings suggest that IL6 may be a promising target for the treatment of metastasis in colorectal cancers by improving host immunity.