Abstract
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.
Highlights
Diabetes and cancer are severe health concerns of worldwide significance
In addition to severe complications caused by chronic hyperglycemia, epidemiological studies show that diabetic patients have higher risk of cancer [1,2,3,4,5,6], suggesting that diabetic patients carry impaired anti-tumor immunity
Our data showed that adoptive transfer of STZdiabetic CD8+ effector cells resulted in fewer tumor-infiltrating T cells as well as less production of perforin, Granzyme B and TNFa in situ
Summary
Diabetes and cancer are severe health concerns of worldwide significance. In addition to severe complications caused by chronic hyperglycemia, epidemiological studies show that diabetic patients have higher risk of cancer [1,2,3,4,5,6], suggesting that diabetic patients carry impaired anti-tumor immunity. Glucose is essential fuel for T cell activation, proliferation, and acquisition of effector functions [11,12,13,14,15]. Whether the diabetic condition hinders CD8+ T cell activation and differentiation into functional effector cells remains undefined. It remains elusive in what extent of CD8+ T cells that are hampered by acute hyperglycemia
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