title: 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.
abstract: 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.
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komohara
authors.affiliation: Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Morita
authors.affiliation: Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Dorcas A
authors.initials: DA
authors.lastname: Annan
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Hasita
authors.initials: H
authors.lastname: Horlad
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ohnishi
authors.affiliation: Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan.
authors.forename: Sohsuke
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Department of Pathology and Cell Biology, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan.
authors.forename: Shohei
authors.initials: S
authors.lastname: Kitada
authors.affiliation: Center for AIDS Research, Kumamoto University, Kumamoto, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Suzu
authors.affiliation: Department of Medical Oncology, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kinoshita
authors.affiliation: Department of Medical Oncology, Hokkaido University School of Medicine, Sapporo, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Dosaka-Akita
authors.affiliation: Department of Medicine and Biosystemic Sciences, Kyushu University Graduate School of Medicine, Fukuoka, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Akashi
authors.affiliation: Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.affiliation: Research Center for Infection-Associated Cancer, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan. Institute for Advanced Medical Research, Keio University Graduate School of Medicine, Tokyo, Japan. jinushi@z7.keio.jp.
authors.forename: Masahisa
authors.initials: M
authors.lastname: Jinushi
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000378:metabolism* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2; D064593:Heterografts; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D011379:Prognosis; D011758:Pyrroles / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D000077210:Sunitinib; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D007211:Indoles; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011758:Pyrroles; D000077210:Sunitinib; D020123:Sirolimus