Functional Change of Effector Tumor-Infiltrating CCR5(+)CD38(+)HLA-DR(+)CD8(+) T Cells in Glioma Microenvironment

Human glioma facilitates an impaired anti-tumor immunity response, including defects in circulation of T lymphocytes. The level of CD8(+) T-cell activation acts as an immune regulator associated with disease progression. However, little is known about the characteristics of peripheral and tumor-infiltrating CD8(+) T cells in patients with glioma. In this study, we examined the level of CD8(+) T-cell activation in a group of 143 patients with glioma and determined that peripheral CD3(+) T cells decreased in accordance with disease severity. The patients' peripheral CD8(+) T-cell populations were similar to that of healthy donors, and a small amount of CD8(+) tumor-infiltrating lymphocytes was identified in glioma tissues. An increase in activated CD8(+) T cells, characterized as CD38(+)HLA-DR(+), and their association with disease progression were identified in the patients' peripheral blood and glioma, and shown to display enriched CCR5(+) and TNFR2(+) expression levels. Ex vivo examination of CD38(+)HLA-DR(+)CD8(+) T cells indicated that this subset of cells displayed stronger secretion of IFN-γ and IL-2 before and after a 6-h stimulation with phorbol 12-myristate 13-acetate (PMA) and ionomycin (ION) relative to healthy CD38(+)HLA-DR(+)CD8(+) T cells, indicating the functional feasibility of CD38(+)HLA-DR(+)CD8(+) T cells. Higher CCL5 protein and mRNA levels were identified in glioma tissues, which was consistent with the immunohistochemistry results revealing both CCL5 and CD38(+)HLA-DR(+)CD8(+) T cell expression. Patients' CCR5(+)CD38(+)HLA-DR(+)CD8(+) T cells were further validated and shown to display increases in CD45RA(+)CCR7(−) and T-bet(+) accompanied by substantial CD107-a, IFN-γ, and Granzyme B levels in response to glioma cells.