Circulating tumor-associated neutrophils (cTAN) contribute to circulating tumor cell survival by suppressing peripheral leukocyte activation

During malignant progression, primary tumors rebuild leukocyte profile and suppress the host anti-tumor immune response. Tumor-associated neutrophils (TAN) increased in the cancer patients and emerged as an important participant and regulator of immune responses. The aim of this study is to investigate the role of circulating TAN (cTAN) in the metastatic process of advanced malignancy. We tested circulating neutrophils from patients (n = 180) with various types of cancer using flow cytometry analyses. We also used B16F10 cell-implanted C57BL/6 tumor-bearing mice model to simulate the advanced malignancy. Peripheral neutrophils were isolated by ficoll density gradient centrifugation, and in vitro tumor-leukocyte co-culture model was used to test tumor cell survival under leukocyte challenge condition. Here, we showed that neutrophils increased in the peripheral blood under the pathological condition of advanced malignancy both in cancer patients and in tumor-bearing mice. In mouse model, the malignantly increased neutrophils were identified as TAN according to the gene transcriptional analyses. We also showed that cTAN enhance tumor metastasis and cTAN could inhibit the activation of the peripheral leukocytes and rescue tumor cells from leukocyte challenge. In conclusion, our finding suggests that the abundance of cTAN in advanced cancer patients contributes to the circulating tumor cell survival by suppressing peripheral leukocyte activation.