Takahashi Hideyuki, Sakakura Koichi, Kudo Takeshi, Toyoda Minoru, Kaira Kyoichi, Oyama Tetsunari, Chikamatsu Kazuaki
Department of Otolaryngology-Head and Neck Surgery, Gunma University Graduate School of Medicine, Gunma, Japan.
Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Gunma, Japan.
Oncotarget. 2017 Jan 31;8(5):8633-8647. doi: 10.18632/oncotarget.14374.
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.
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行为。我们在此研究了癌症相关成纤维细胞（CAFs）在体外和人类癌症样本中影响口腔鳞状细胞癌（OSCC）中肿瘤相关巨噬细胞（TAMs）功能极化的机制。与从OSCC标本建立的CAFs培养上清液共培养的CD14阳性细胞（CAF诱导细胞）中，CD68、CD14、CD163、CD200R、CD206、HLA - G、CD80和CD86的表达高于对照细胞。CAF诱导细胞中ARG1、IL10和TGFB1的基因表达水平升高。CAF诱导细胞比对照细胞更强烈地抑制T细胞增殖，而中和TGF -β、IL - 10或精氨酸酶I可显著恢复T细胞增殖。然后，我们使用从OSCC患者获得的组织样本研究了CAFs和TAMs浸润之间的关系。CAFs的浸润与CD68阳性和CD163阳性巨噬细胞的数量相关。它还与淋巴浸润、血管浸润、淋巴结受累和TNM分期相关。CAFs的浸润被确定为OSCC的独立预后因素。我们的结果表明，CAFs通过诱导TAMs的促肿瘤表型在塑造OSCC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。
