Defects in the Acquisition of Tumor-Killing Capability of CD8+ Cytotoxic T Cells in Streptozotocin-Induced Diabetic Mice

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.

Hyperglycaemia does not affect antigen-specific activation and cytolytic killing by CD8+ T cells in vivo

“…In vivo CD8 + T-cell proliferation and cytokine production was unaffected in diabetic C57BL/6, as was in vivo cytolytic killing. This finding is in contrast with a previous study, which demonstrated greater survival of tumour cells in STZ-induced diabetic mice [ 18 ]. It is however possible that the elevated glucose levels in diabetic mice affect not only CTL but also the tumour cells, and this may contribute to their greater survival.…”

“…An important point to make here is the difference between STZ protocols. Many groups administer one high dose of 200 µg/g body weight [ 18 – 20 ] and may see a resulting down-regulation of immune responses. STZ is a glucosamine–nitrosourea that causes DNA damage, and is particularly toxic to β-cells as it is taken up via the Glut2 transporter, which is expressed in β-cells and to a lower extent in kidney, liver and small intestine.…”

Attenuation of NK cells facilitates mammary tumor growth in streptozotocin-induced diabetes in mice

“…Further, we tested the cytotoxicity of isolated CD8 + T cells and NK cells. Recently, using melanoma model, Chen and coworkers have shown that the acquisition of tumor-killing capacity of CD8 + T cytotoxic cells is diminished in melanoma-bearing STZdiabetic mice (Chen et al 2014). However, we did not find any significant difference in cytotoxicity of CD8 + T cells to mammary tumor cells in vitro (Fig.…”

“…Previous evidence in mice and humans clearly demonstrated the relationship between type 1 and type 2 diabetes and malignancy and some studies have investigated the underlying mechanisms (Ikemura et al 2013, Chen et al 2014. The study by Goto and coworkers demonstrated that STZ-induced diabetes accelerates mammary tumor genesis; however, the cellular basis of this effect was not explored (Goto et al 1995).…”

“…Type 1 diabetic patients have decreased expression and aberrant signaling through the NKG2D receptor as well as markedly lower expression of p30/p46 NK-activating receptor molecules (Rodacki et al 2007, Qin et al 2011). Chen and coworkers have shown that stimulated streptozotocin (STZ)diabetic cytotoxic T cells produce less perforin and TNF-α and thus they have no capability to eliminate melanoma cells and improve the survival of tumor-bearing mice (Chen et al 2014). Other studies have shown that diabetes decreases total percentage and also impairs the expression of chemokine receptors and costimulatory molecules and decreases the production of proinflammatory cytokines in professional antigen-presenting cells (Nieminen et al 2012, Sun et al 2012.…”