Cancer-associated fibroblasts promote PD-L1 expression in mice cancer cells via secreting CXCL5
Cancer-associated fibroblasts promote PD-L1 expression in mice cancer cells via secreting CXCL5
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癌症相关成纤维细胞通过分泌CXCL5促进小鼠癌细胞中PD-L1的表达
DOI：
10.1002/ijc.32278
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发表时间：
2019-10-01
影响因子：
6.4
通讯作者：
Du, Jun
中科院分区：
文献类型：
--
作者：
Li, Ziqian;Zhou, Jiawang;Du, Jun
肿瘤相关成纤维细胞(CAF)在肿瘤微环境中对肿瘤的恶性生物学特性起着关键作用，有证据表明CAF是肿瘤免疫抑制T细胞反应的重要调节因子。然而，CAF在黑色素瘤和结直肠癌(CRC)中对程序性死亡配体1(PD-L1)表达的作用和调控尚不完全清楚。在这里，通过仔细观察黑色素瘤和结直肠癌组织中α-SMA和PD-L1的表达，我们发现CAF与PD-L1的表达呈正相关。进一步的分析表明，CAF促进了小鼠肿瘤细胞中PD-L1的表达。通过检测正常小鼠成纤维细胞和CAF中大多数细胞因子的表达，我们确定CXCL5在CAF中异常高表达，免疫组织化学和原位杂交证实CXCL5在CAF中表达。此外，CXCL5还可促进B16、CT26、A375和HCT116细胞中PD-L1的表达。CXCL5受体CXCR2的沉默依次抑制CAF诱导的PD-L1表达。在功能上，CAF衍生的CXCL5通过激活PI3K/AKT信号通路促进小鼠肿瘤细胞PD-L1的表达。PI3K的抑制剂LY294002证实，CXCL5通过PI3K/AKT信号途径促进PD-L1的表达，从而形成免疫抑制微环境。同时，采用B16/CT26移植瘤模型，发现CXCR2和p-AKT在移植瘤组织中均与PD-L1呈正相关。CAF对肿瘤细胞的免疫抑制作用可能反映了它们是治疗黑色素瘤和结直肠癌的潜在治疗生物标志物。
Cancer-associated fibroblasts (CAFs) play a key role in orchestrating the tumor malignant biological properties within tumor microenvironment and evidences demonstrate that CAFs are a critical regulator of tumoral immunosuppression of the T cell response. However, the functions and regulation of CAFs in the expression of programmed death-ligand 1 (PD-L1) in melanoma and colorectal carcinoma (CRC) are not completely understood. Herein, by scrutinizing the expression of alpha-SMA and PD-L1 in melanoma and CRC tissues, we found that CAFs was positive correlated with PD-L1 expression. Further analyses showed that CAFs promoted PD-L1 expression in mice tumor cells. By detecting a majority of cytokines expression in normal mice fibroblasts and CAFs, we determined that CXCL5 was abnormal high expression in CAFs and the immunohistochemistry and in situ hybridization confirmed that were CAFs which were expressing CXCL5. In addition, CXCL5 promoted PD-L1 expression in B16, CT26, A375 and HCT116. The silencing of CXCR2, the receptor of CXCL5, inhibited the PD-L1 expression induced by CAFs in turn. Functionally, CXCL5 derived by CAFs promoted PD-L1 expression in mice tumor cells through activating PI3K/AKT signaling. LY294002, the inhibitor of PI3K, confirmed that CXCL5 forested an immunosuppression microenvironment by promoting PD-L1 expression via PI3K/AKT signaling. Meanwhile, the B16/CT26 xenograft tumor models were used and both CXCR2 and p-AKT were found to be positively correlated with PD-L1 in the xenograft tumor tissues. The immunosuppressive action of CAFs on tumor cells is probably reflective of them being a potential therapeutic biomarker for melanoma and CRC.