CD8⁺CD57⁺ T cells exhibit distinct features in human non-small cell lung cancer

Abstract

BackgroundThe 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.MethodsWe 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.ResultsCD57+ 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.ConclusionsOur 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.

Senescent T cells: a potential biomarker and target for cancer therapy

“…Senescent T cells lose the expression of costimulatory receptors CD27/CD28 but express CD57 and KLRG-1, which indicates replicative senscent [2] , [3] , [4] . Senescent T cells also show a terminally differentiated phenotype with the downregulation of the chemokine receptors CCR7 and CD45RO but the upregulation of CD45RA [ 17 , 22 , 23 ]. Therefore, the T cell phenotype of CD27 − CD28 − CD57 + KLRG-1 + , or CCR7 − CD45RA + is a commonly used indicator of T cell senescence.…”

“…Senescent T cells accumulate in the peripheral blood of patients with solid tumour, such as lung cancer [22] , breast cancer [42 , 43] , head and neck cancer [44] , gastric cancer [45] , glioblastoma [46] , and haematologic malignancies, such as acute myeloid leukaemia (AML) [47 , 48] , and chronic lymphocytic leukaemia (CLL) [49 , 50] , and increase with clinical stage [51] . Senescent T cells show a decreasing tendency after tumour resection [44] or in long-term complete remission (CR) [47] .…”

“…Senescent T cells show a decreasing tendency after tumour resection [44] or in long-term complete remission (CR) [47] . T cells also display features of senescence at the tumour site of non-small cell lung cancer (NSCLC) [22] , multiple myeloma [52] , ovarian cancer [2] , breast cancer [2] , and follicular lymphoma [53] . In NSCLC, although the percentage of CD57 + T cells in CD3 + tumour-infiltrating lymphocytes (TILs) is lower than that observed in the peripheral blood [22] , the cytokine production and proliferation ability of senescent T cells is much more dampened at the tumour site [22 , 52] .…”

“…T cells also display features of senescence at the tumour site of non-small cell lung cancer (NSCLC) [22] , multiple myeloma [52] , ovarian cancer [2] , breast cancer [2] , and follicular lymphoma [53] . In NSCLC, although the percentage of CD57 + T cells in CD3 + tumour-infiltrating lymphocytes (TILs) is lower than that observed in the peripheral blood [22] , the cytokine production and proliferation ability of senescent T cells is much more dampened at the tumour site [22 , 52] . In vitro experiments further confirmed that tumour cells [ 14 , 16 , 38 , 48 ] or Tregs in the tumour microenvironment [11 , 13] are able to induce T cell senescence.…”

Immunological profiling of COVID-19 patients with pulmonary sequelae

“…Furthermore, CD4+ T cells, CD8+ T cells, NK cells, NKT cells and γδ T cells secreting GZMB and perforin were enriched among CD57+ cells, CD28-cells and CD27-cells. Although peripheral blood CD57+ T cells exhibit phenotypic and functional features of terminally differentiated effector cells, these cells display enhanced cytotoxic function(47-49). Moreover, GZMB and perforin expression exhibited intrinsic positive correlations among CD4+ T cells, CD8+ T cells, NK cells, NKT cells and γδ T cells, suggesting that SARS-CoV-2 infection may simultaneously activate a variety of immune cells.…”