Cancer-Associated Fibroblasts Affect Intratumoral CD8+ and FoxP3+ T Cells Via IL6 in the Tumor Microenvironment
Cancer-Associated Fibroblasts Affect Intratumoral CD8+ and FoxP3+ T Cells Via IL6 in the Tumor Microenvironment
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DOI：
10.1158/1078-0432.ccr-18-0205
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发表时间：
2018-10-01
影响因子：
11.5
通讯作者：
Fujiwara, Toshiyoshi
中科院分区：
文献类型：
--
作者：
Kato, Takuya;Noma, Kazuhiro;Fujiwara, Toshiyoshi
目的：肿瘤微环境(TME)中的肿瘤相关成纤维细胞(CAF)在肿瘤进展中起核心作用。研究CAF对肿瘤浸润性淋巴细胞(TIL)的调节作用及其在肿瘤免疫抑制中的作用。实验设计：对140例食道癌患者进行CAFS和CD8(+)或FoxP3(FoxP3)TIL的免疫组化检测。我们使用小鼠或人类成纤维细胞和癌细胞来分析细胞因子。结果：食道癌组织中CD8+TIL与CAF呈负相关(P<0.001)，FoxP3(+)TIL与FoxP3(+)TIL呈正相关(P<0.001)。与单独培养的癌细胞相比，共培养的Colon26癌细胞和成纤维细胞可加速BALB/c小鼠的肿瘤生长，同时降低CD8(+)和增加FoxP3(+)TIL。在体外，IL6在小鼠和人癌细胞/成纤维细胞共培养中都能高水平分泌。在免疫功能良好的BALB/c(P<；0.001)中，IL-6显著促进了COLON2G肿瘤的生长，其CD8(+)TIL比未经治疗的肿瘤(P<；0.001)少，而在BALB/c-nu/nu小鼠中没有差异。相反，在IL6治疗的肿瘤中，FoxP3(+)TIL增加(P<；0.001)。IL 6抗体阻断肿瘤与成纤维细胞共培养后，不仅肿瘤生长减退，而且肿瘤组织中CD8(+)TLI积聚。结论：CAF通过IL6调节TME中的免疫抑制TIL细胞。阻断IL6或靶向CAF，可能会改善原有的肿瘤免疫，并增强传统免疫疗法的疗效。(C)2018年AACR。
Purpose: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a central role in tumor progression. We investigated whether CAFs can regulate tumorinfiltrating lymphocytes (TILs) and their role in tumor immunosuppression.Experimental Design: A total of 140 cases of esophageal cancer were analyzed for CAFs and CD8(+) or forkhead box protein 3 (FoxP3) TILs by IHC. We analyzed cytokines using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c-nu/nu mice and the tumors treated with recombinant IL6 or anti-IL6 antibody.Results: CD8(+) TILs and CAFs were negatively correlated in intratumoral tissues (P < 0.001), whereas FoxP3(+) TILs were positively correlated (P < 0.001) in esophageal cancers. Cocultured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8(+) and increased FoxP3(+) TILs, compared with cancer cells alone. In vitro, IL6 was highly secreted in both murine and human cancer cell/fibroblast cocultures. IL6 significantly increased Colon2G tumor growth in immune-competent BALB/c (P < 0.001) with fewer CD8(+) TILs than untreated tumors (P < 0.001), whereas no difference in BALB/c-nu/nu mice. In contrast, FoxP3(+) TILs increased in IL6-treated tumors (P < 0.001). IL6 antibody blockade of tumors cocultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8(+) TLIs in intratumoral tissues.Conclusions: CAFs regulate immunosuppressive TIL populations in the TME via IL6. IL6 blockade, or targeting CAFs, may improve preexisting tumor immunity and enhance the efficacy of conventional immunotherapies. (C)2018 AACR.