Defects in the acquisition of tumor-killing capability of CD8+ cytotoxic T cells in streptozotocin-induced diabetic mice
Journal
PLoS ONE
Journal Volume
9
Journal Issue
11
Date Issued
2014
Author(s)
Su Y.-C.
Lu Y.-T.
Chang P.-Y.
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 streptozotocininduced 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 TNFa 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. ? 2014 Chen et al.
SDGs
Other Subjects
CD103 antigen; granzyme B; perforin; streptozocin; T lymphocyte receptor; tumor necrosis factor alpha; alpha E integrins; alpha integrin; cytokine; leukocyte antigen; lymphocyte antigen receptor; adoptive transfer; animal cell; animal experiment; animal model; animal tissue; Article; C57BL 6 mouse; CD8+ T lymphocyte; cell proliferation; controlled study; cytotoxic T lymphocyte; hyperglycemia; immunohistochemistry; lymphocyte proliferation; lymphoid tissue; male; mouse; nonhuman; protein expression; streptozotocin-induced diabetes mellitus; survival; transgenic mouse; tumor associated leukocyte; animal; C57BL mouse; CD8+ T lymphocyte; cell differentiation; chemistry; cytology; cytotoxic T lymphocyte; experimental diabetes mellitus; experimental melanoma; immunology; metabolism; Mus; Adoptive Transfer; Animals; Antigens, CD; CD8-Positive T-Lymphocytes; Cell Differentiation; Cell Proliferation; Cytokines; Diabetes Mellitus, Experimental; Hyperglycemia; Integrin alpha Chains; Lymphocytes, Tumor-Infiltrating; Male; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Mice, Transgenic; Receptors, Antigen, T-Cell; Streptozocin; T-Lymphocytes, Cytotoxic
Publisher
Public Library of Science
Type
journal article