Clear cell renal cell carcinoma (ccRCC) is one of most common cancers in urogenital organs. Although recent experimental and clinical studies showed the immunogenic properties of ccRCC as shown 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 Ig 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 (TAMs) and higher expression level of TIM-3 was well correlated with shorter progression-free survival (PFS) among patients with ccRCC. We found that TIM-3 expression was detected on the large numbers of tumors, and there was significant correlation between an increased numbers 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 the in vitro and in vivo settings. These findings indicate the coordinated action of TIM-3 in cancer and myeloid cells regulate the tumorigenicity of human RCC.
- Received August 24, 2014.
- Revision received February 1, 2015.
- Accepted March 4, 2015.
- Copyright © 2015, American Association for Cancer Research.