Abstract
BACKGROUND: Interleukin (IL)-7 signaling through CD127 is impaired in lymphocytes in cancers and chronic infections, resulting in CD8(+) T cell exhaustion. The mechanisms underlying CD8(+) T cell responses to IL-7 in melanoma remain not completely elucidated. We previously showed reduced IL-7 level in melanoma patients. Thus, the aim of this study was to investigate the effect of IL-7 regulation on CD127 expression and CD8(+) T cell responses in melanoma. METHODS: Healthy controls and primary cutaneous melanoma patients were enrolled. Membrane-bound CD127 (mCD127) expression on CD8(+) T cells was determined by flow cytometry. Soluble CD127 (sCD127) protein level was measured by ELISA. Total CD127 and sCD127 mRNA level was measured by real-time PCR. CD8(+) T cells were stimulated with recombinant human IL-7, along with signaling pathway inhibitors. CD8(+) T cells were co-cultured with melanoma cell line, and the cytotoxicity of CD8(+) T cells was assessed by measurement of lactate dehydrogenase expression. RESULTS: Plasma sCD127 was lower in melanoma patients compared with controls. The percentage of CD8(+) T cells expressing mCD127 was higher, while sCD127 mRNA level was lower in peripheral and tumor-infiltrating CD8(+) T cells from melanoma patients. There was no significant difference of total CD127 mRNA expression in CD8(+) T cells between groups. IL-7 stimulation enhanced total CD127 and sCD127 mRNA expression and sCD127 release by CD8(+) T cells. However, mCD127 mRNA expression on CD8(+) T cells was not affected. This process was mainly mediated by phosphatidylinositol 3-kinase (PI3K) pathway. CD8(+) T cells from melanoma patients exhibited decreased cytotoxicity. IL-7 stimulation promoted CD8(+) T cell cytotoxicity, while inhibition of PI3K dampened IL-7-induced elevation of CD8(+) T cell cytotoxicity. CONCLUSION: The current data suggested that insufficient IL-7 secretion might contribute to CD8(+) T cell exhaustion and CD127 dysregulation in patients with primary cutaneous melanoma.