Docetaxel Down-Regulates PD-1 Expression via STAT3 in T Lymphocytes

In patients with non small-cell lung cancer, docetaxel therapy decreases several inhibitory receptors of T cells, including T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and T-cell immunoglobulin and mucin domain 3 (TIM-3). In vitro assay indicated that PD-1 is directly regulated by docetaxel via signal transducer and activator of transcription 3 (STAT3) signaling. Our results support the notion that chemotherapy could help modulate the immune status of cancer patients. Background: Lung tumor is a major cause of cancer incidence and patient death. Chemotherapy is the primary therapy used to treat lung cancer. In addition to direct cytotoxic effect on tumor cells, chemotherapeutic drugs activate immune responses to exert antitumor function. Here, the effects of docetaxel on the inhibitory molecules, programmed cell death 1 (PD-1), cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), and T-cell immunoglobulin and mucin domain 3 (TIM-3) in T lymphocytes were explored in patients with lung adenocarcinoma. Patients and Methods: Peripheral blood mononuclear cells were isolated from lung adenocarcinoma patients receiving cisplatin-docetaxel chemotherapy. By flow cytometry and PCR, the expressions of CTLA-4, PD-1 and TIM-3 in T cell subsets were analyzed. Health subjects were used as control group. Results: During chemotherapy, suppressive markers were down-regulated in peripheral CD4' and CD8' T cells from patients with partial remission or stable disease. Additionally, interferon-y production was also augmented during this period. In vitro assay showed that docetaxel reduced the expression of PD-1 on T-cell subsets without altering cell death. Further tests in Jurkat T cells demonstrated that docetaxel activated signal transduction and activator of transcription 3 (STAT3) signaling to suppress PD1 expression, whereas STAT3 inhibition reversed the down-regulation of PD-1. Conclusion: Our data support the hypothesis that chemotherapeutic drugs are not only purely cytotoxic but are also immune modulators. (C) 2018 Elsevier Inc. All rights reserved.