title: Tim-3 expression represents dysfunctional tumor infiltrating T cells in renal cell carcinoma.
abstract: OBJECTIVE
  Renal cell carcinoma (RCC) is the most common cancer of kidney. Evidences have shown that RCC is sensitive to various immunotherapies. Tim-3 plays a role in suppressing Th1-mediated immune responses. However, no study has yet examined the effect of Tim-3 on tumor infiltrating lymphocytes (TILs) in RCC.
  
  
  METHODS
  We investigated the expression and function of Tim-3 on TIL CD4+ T cells and TIL CD8+ T cells from 30 RCC patients.
  
  
  RESULTS
  Levels of Tim-3 were significantly increased on both TIL CD4+ T cells and TIL CD8+ T cells and were associated with higher stages of the cancer. Also, GATA-3 and interferon gamma (IFN-γ) were down-regulated, whereas T-bet was up-regulated in TIL Tim-3+ T cells, indicating that Tim-3 expression defined a population of dysfunctional TIL Th1/Tc1 cells. Mechanism analyses showed that TIL Tim-3-expressing CD8+ T cells exhibited impaired Stat5 and p38 signaling pathway. Blocking the Tim-3 pathway restored cell proliferation and increased IFN-γ production in TIL CD4+ and CD8+ T cells of RCC.
  
  
  CONCLUSIONS
  These results suggest that Tim-3 may be used as a novel target for increasing immune responses in RCC tumor microenvironment.
authors.affiliation: Department of Special Clinic, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Cai
authors.affiliation: Department of Urology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China.
authors.forename: Yi-Fan
authors.initials: YF
authors.lastname: Xu
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China.
authors.forename: Zhen-Jie
authors.initials: ZJ
authors.lastname: Wu
authors.affiliation: Department of Nephrology, Shanghai Corps Hospital, Chinese People's Armed Police Forces, Shanghai, 201103, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Dong
authors.affiliation: Department of Special Clinic, Changhai Hospital, Second Military Medical University, Shanghai, 200433, China.
authors.forename: Min-Yu
authors.initials: MY
authors.lastname: Li
authors.affiliation: Georgetown University School of Medicine, Washington, DC, 20007, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Olson
authors.affiliation: Georgetown University School of Medicine, Washington, DC, 20007, USA. Yaron.Rabinowitz@gmail.com.
authors.forename: Yaron M
authors.initials: YM
authors.lastname: Rabinowitz
authors.affiliation: Department of Urology, Changzheng Hospital, Second Military Medical University, Shanghai, 200003, China. wanglinhuicz@163.com.
authors.forename: Lin-Hui
authors.initials: LH
authors.lastname: Wang
authors.affiliation: Department of Urology, Changhai Hospital, Second Military Medical University, 168 Changhai Road, Shanghai, 200433, China.
authors.forename: Yinghao
authors.initials: Y
authors.lastname: Sun
mesh_terms: D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012334:RNA, Neoplasm / Q000235:genetics*
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D012334:RNA, Neoplasm
keywords: Renal cell carcinoma; Tim-3; Tumor infiltrating lymphocytes