The Coordinated Actions of TIM-3 on Cancer and Myeloid Cells in the Regulation of Tumorigenicity and Clinical Prognosis in Clear Cell Renal Cell Carcinomas
The Coordinated Actions of TIM-3 on Cancer and Myeloid Cells in the Regulation of Tumorigenicity and Clinical Prognosis in Clear Cell Renal Cell Carcinomas
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DOI：
10.1158/2326-6066.cir-14-0156
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发表时间：
2015-09-01
影响因子：
10.1
通讯作者：
Jinushi, Masahisa
中科院分区：
文献类型：
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作者：
Komohara, Yoshihiro;Morita, Tomoko;Jinushi, Masahisa
肾透明细胞癌（Clear cell renal cell carcinoma，ccRCC）是泌尿生殖系统最常见的恶性肿瘤之一。尽管最近的实验和临床研究已经显示了ccRCC的免疫原性，如对各种免疫疗法的临床敏感性所示，但控制人ccRCC致瘤性的详细免疫调节机制在很大程度上仍然不清楚。在这项研究中，我们证明了ccRCC患者肿瘤细胞和骨髓细胞上表达的T细胞免疫球蛋白和含粘蛋白结构域的分子-3（TIM-3）的临床意义和功能相关性。在癌细胞和CD 204（+）肿瘤相关巨噬细胞（TAM）上检测到TIM-3表达，并且在ccRCC患者中，TIM-3的较高表达水平与较短的无进展生存期（PFS）正相关。我们发现在大量肿瘤上检测到TIM-3表达，并且在ccRCC患者中TAM数量增加与TIM-3的高表达水平之间存在显著相关性。此外，TIM-3使RCC细胞具有诱导对舒尼替尼和mTOR抑制剂（ccRCC患者的标准方案）的抗性以及干细胞活性的能力。在RCC细胞的长期刺激下，CD 14（+）单核细胞上的TIM-3表达被诱导，并且表达TIM-3的髓样细胞在增加TIM-3阴性RCC细胞的致瘤活性中起关键作用。更重要的是，用抗TIM-3 mAb治疗抑制了其在体外和体内环境中的致瘤作用。这些发现表明TIM-3在癌细胞和骨髓细胞中的协调作用调节人RCC的致瘤性。(C)2015年AACR。
Clear cell renal cell carcinoma (ccRCC) is one of most common cancers in urogenital organs. Although recent experimental and clinical studies have shown the immunogenic properties of ccRCC as illustrated by the clinical sensitivities to various immunotherapies, the detailed immunoregulatory machineries governing the tumorigenicity of human ccRCC remain largely obscure. In this study, we demonstrated the clinical significance and functional relevance of T-cell immunoglobulin and mucin domain-containing molecule-3 (TIM-3) expressed on tumor cells and myeloid cells in patients with ccRCC. TIM-3 expression was detected on cancer cells and CD204(+) tumor-associated macrophages (TAM), and higher expression level of TIM-3 was positively correlated with shorter progression-free survival (PFS) in patients with ccRCC. We found that TIM-3 expression was detected on a large number of tumors, and there was significant correlation between an increased number of TAMs and high expression level of TIM-3 in patients with ccRCC. Furthermore, TIM-3 rendered RCC cells with the ability to induce resistance to sunitinib and mTOR inhibitors, the standard regimen for patients with ccRCC, as well as stem cell activities. TIM-3 expression was induced on CD14(+) monocytes upon long-term stimulation with RCC cells, and TIM-3-expressing myeloid cells play a critical role in augmenting tumorigenic activities of TIM-3-negative RCC cells. More importantly, treatment with anti-TIM-3 mAb suppressed its tumorigenic effects in in vitro and in vivo settings. These findings indicate the coordinated action of TIM-3 in cancer cells and in myeloid cells regulates the tumorigenicity of human RCC. (C) 2015 AACR.