Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer.
TIM-3 functions to enforce CD8+ T cell exhaustion, a dysfunctional state associated with the tolerization of tumor microenvironment. Here we report apoptosis of IFN-γ competent TIM-3+ population of tumor-infiltrating CD8+ T cells in colon cancer. In humans suffering from colorectal cancer, TIM-3+ population is higher in cancer tissue-resident relative to peripheral blood CD8+ T cells. Both the TIM-3+ and TIM-3- cancer tissue-resident CD8+ T cells secrete IFN-γ of comparable levels, although apoptotic cells are more in TIM-3+ compared to TIM-3- population. In mouse CT26 colon tumor model, majority of tumor-infiltrating CD8+ T cells express TIM-3 and execute cytolysis function with higher effector cytokine secretion and apoptosis in TIM-3+ compared to TIM-3- population. The tumor cells secrete galectin-9, which increases apoptosis of tumor-infiltrating CD8+ T cells. Galectin-9/TIM-3 signaling blockade with anti-TIM-3 antibody reduces the apoptosis and in addition, inhibits tumor growth in mice. The blockade increases therapeutic efficacy of cyclophosphamide to treat tumor in mice as well. These results reveal a previously unexplored role of TIM-3 on tumor-infiltrating CD8+ T cells in vivo.
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kweishan- 333, Taoyuan, Taiwan.|Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kweishan- 333, Taoyuan, Taiwan.
Chiao-Wen
CW
Kang
Division of Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital and Chang Gung University, Kweishan- 333, Taoyuan, Taiwan.
Avijit
A
Dutta
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kweishan- 333, Taoyuan, Taiwan.|Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kweishan- 333, Taoyuan, Taiwan.
Li-Yuan
LY
Chang
Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kweishan- 333, Taoyuan, Taiwan.
Jayashri
J
Mahalingam
Division of Hematooncology, Department of Medicine, Chang Gung Memorial Hospital and Chang Gung University, Kweishan, 333, Taoyuan, Taiwan.
Yung-Chang
YC
Lin
Colorectal Surgery Section, Department of Surgery, Chang Gung Memorial Hospital and Chang Gung University, Kweishan- 333, Tayouan, Taiwan.
Jy-Ming
JM
Chiang
Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kweishan- 333, Taoyuan, Taiwan.
Chen-Yu
CY
Hsu
Division of Infectious Diseases, Department of Medicine, Chang Gung Memorial Hospital and Chang Gung University, Kweishan- 333, Taoyuan, Taiwan.
Ching-Tai
CT
Huang
Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kweishan- 333, Taoyuan, Taiwan.
Wan-Ting
WT
Su
Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kweishan- 333, Taoyuan, Taiwan.
Yu-Yi
YY
Chu
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kweishan- 333, Taoyuan, Taiwan.|Division of Hepatogastroenterology, Department of Internal Medicine, Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Kweishan- 333, Taoyuan, Taiwan.
Chun-Yen
CY
Lin
D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003110:Colonic Neoplasms / Q000276:immunology* / Q000473:pathology; D037161:Galectins / Q000502:physiology; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000276:immunology*
D037161:Galectins; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105032:LGALS9 protein, human; D008565:Membrane Proteins