Defects in the acquisition of tumor-killing capability of CD8+ cytotoxic T cells in streptozotocin-induced diabetic mice.
Emerging evidences have shown that diabetes mellitus not only raises risk but also heightens mortality rate of cancer. It is not clear, however, whether antitumor CD8+ cytotoxic T lymphocyte (CTL) response is down-modulated in diabetic hosts. We investigated the impact of hyperglycemia on CTLs' acquisition of tumor-killing capability by utilizing streptozotocin-induced diabetic (STZ-diabetic) mice. Murine diabetes was induced by intraperitoneal injection of STZ (200 mg/kg) in C57BL/6 mice, 2C-T cell receptor (TCR) transgenic and P14-TCR transgenic mice. The study found that, despite harboring intact proliferative capacity measured with CFSE labeling and MTT assay, STZ-diabetic CD8+ CTLs displayed impaired effector functions. After stimulation, STZ-diabetic CD8+ CTLs produced less perforin and TNFα assessed by intracellular staining, as well as expressed less CD103 protein. Furthermore, adoptive transfer of STZ-diabetic P14 CD8+ effector cells showed an insufficient recruitment to the B16.gp33 melanoma and inadequate production of perforin, granzyme B and TNFα determined by immunohistochemistry in the tumor milieu. As a result, STZ-diabetic CD8+ effector cells were neither able to eliminate tumor nor to improve survival of tumor-bearing mice. Taken together, our data suggest that CD8+ CTLs are crippled to infiltrate into tumors and thus fail to acquire tumor-killing capability in STZ-diabetic hosts.
Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Shu-Ching
SC
Chen
National Laboratory Animal Center, National Applied Research Laboratories, Taipei, Taiwan.
Yu-Chia
YC
Su
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Ya-Ting
YT
Lu
Department of Emergency Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Patrick Chow-In
PC
Ko
Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan.
Pei-Yu
PY
Chang
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Hung-Ju
HJ
Lin
Department of Obstetrics and Gynecology, National Taiwan University, College of Medicine, Taipei, Taiwan.
Hong-Nerng
HN
Ho
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Yo-Ping
YP
Lai
D019264:Adoptive Transfer; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology*; D002454:Cell Differentiation; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D006943:Hyperglycemia / Q000276:immunology; D039001:Integrin alpha Chains / Q000378:metabolism; D016246:Lymphocytes, Tumor-Infiltrating / Q000166:cytology*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D013311:Streptozocin / Q000737:chemistry; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology*
D015703:Antigens, CD; D016207:Cytokines; D039001:Integrin alpha Chains; D011948:Receptors, Antigen, T-Cell; C091367:alpha E integrins; D013311:Streptozocin