Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages.
Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages.
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DOI：
10.18632/oncotarget.14374
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发表时间：
2017-01-31
期刊：
影响因子：
--
通讯作者：
Chikamatsu K
中科院分区：
文献类型：
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作者：
Takahashi H;Sakakura K;Kudo T;Toyoda M;Kaira K;Oyama T;Chikamatsu K
肿瘤微环境（TME）中的基质细胞与肿瘤细胞密切相互作用，并以多种方式影响肿瘤细胞的行为。我们在此研究了癌症相关成纤维细胞（CAFs）影响体外口腔鳞状细胞癌（OSCC）和人类癌症样本中肿瘤相关巨噬细胞（TAMs）功能极化的机制。在与从OSCC标本建立的CAF的培养上清液共培养的CD14阳性细胞（CAF训练细胞）中，CD68、CD14、CD163、CD200 R、CD206、HLA-G、CD80和CD86的表达高于对照细胞。在CAF培养的细胞中，ARG1、IL10和TGFB1的基因表达水平增加。CAF训练的细胞比对照细胞更强烈地抑制T细胞增殖，并且TGF-β IL-10或β-淀粉酶I的中和显著地恢复了T细胞增殖。然后，我们研究了CAFs和TAM的浸润之间的关系，使用从OSCC患者获得的组织样本。CAFs的浸润与CD68阳性和CD163阳性巨噬细胞的数量有关。与淋巴管浸润、血管浸润、淋巴结转移及TNM分期有关。CAFs的浸润是影响口腔鳞癌预后的独立因素。我们的研究结果表明，CAFs通过诱导TAMs的促肿瘤表型，在塑造OSCC中的肿瘤免疫抑制微环境中发挥重要作用。需要考虑逆转CAF介导的免疫抑制的治疗策略。
Stromal cells in the tumor microenvironment (TME) closely interact with tumor cells and affect tumor cell behavior in diverse manners. We herein investigated the mechanisms by which cancer-associated fibroblasts (CAFs) affect the functional polarization of tumor-associated macrophages (TAMs) in oral squamous cell carcinoma (OSCC) in vitro and in human cancer samples. The expression of CD68, CD14, CD163, CD200R, CD206, HLA-G, CD80, and CD86 was higher in CD14-positive cells co-cultured with the culture supernatants of CAFs established from OSCC specimens (CAF-educated cells) than in control cells. The gene expression level of ARG1, IL10, and TGFB1 was increased in CAF-educated cells. CAF-educated cells suppressed T cell proliferation more strongly than control cells, and the neutralization of TGF-β IL-10, or arginase I significantly restored T cell proliferation. We then investigated the relationship between the infiltration of CAFs and TAMs using tissue samples obtained from patients with OSCC. The infiltration of CAFs was associated with the numbers of CD68-positive and CD163-positive macrophages. It also correlated with lymphatic invasion, vascular invasion, lymph node involvement, and the TNM stage. The infiltration of CAFs was identified as an independent prognostic factor in OSCC. Our results indicate that CAFs play important roles in shaping the tumor immunosuppressive microenvironment in OSCC by inducing the protumoral phenotype of TAMs. Therapeutic strategies to reverse CAF-mediated immunosuppression need to be considered.