Abstract
BACKGROUND: The repetitive antigen stimulation during chronic infection often leads to the accumulation of CD8(+)CD57(+) T cells. These cells express high levels of interferon-γ, granzyme B and perforin with elevated cytolytic effect, and are considered as the most potent cells for combating chronical viral infection. The status of CD8(+)CD57(+) T cells in non-small cell lung cancer (NSCLC) has not been well defined. METHODS: We used flow cytometry and undertook a systemic approach to examine the frequency, immunophenotyping and functional properties of CD8(+)CD57(+) T cells in the peripheral blood, tumor tissue and the corresponding normal tissue, as well as lung draining lymph nodes, of patients with NSCLC. RESULTS: CD57(+) T cells expressed high levels of programmed cell death-1 (PD-1) in all tested compartments and were predominantly CD8(+) T cells. These cells in the peripheral blood displayed a terminally differentiated phenotype as defined by loss of CD27 and CD28 while expressing KLRG1. CD8(+)CD57(+) T cells exhibited enhanced cytotoxic potencies and impaired proliferative capability. Unlike CD57(+) T cells in the peripheral blood, a significant proportion of CD57(+) T cells in the primary tumors expressed CD27 and CD28. CD8(+)CD57(+) T cells in tumors lacked cytotoxic activity. The proliferative activity of these cells was also impaired. CD8(+)CD57(+) T cells in the corresponding normal lung tissues shared similarities with their counterparts in peripheral blood rather than their counterparts in tumors. The vast majority of CD8(+)CD57(+) T cells in lung draining lymph nodes were positive for CD27 and CD28. These cells were unable to produce perforin and granzyme B, but their proliferative activity was preserved. CD8(+)CD57(+) T cells in tumors displayed an inferior response to PD-1 blockade compared with their CD8(+)CD57(-) counterparts. Interleukin (IL)-15 preferentially restored the effector function of these cells. Additionally, IL-15 was able to restore the impaired proliferative activity of CD8(+)CD57(+) T cells in tumors and peripheral blood. CONCLUSIONS: Our data indicate that the failure of the immune system to fight cancer progression could be a result of impaired CD8(+) T-cell functional maturation into fully differentiated effector T cells within the tumor microenvironment. Boosting IL-15 activity might promote tumor-reactive CD8(+) T-cell functional maturation while preserving their proliferative activity.