Neutrophils in cancer carcinogenesis and metastasis

Abstract

In recent years, neutrophils have attracted increasing attention because of their cancer-promoting effects. An elevated neutrophil-to-lymphocyte ratio is considered a prognostic indicator for patients with cancer. Neutrophils are no longer regarded as innate immune cells with a single function, let alone bystanders in the pathological process of cancer. Their diversity and plasticity are being increasingly recognized. This review summarizes previous studies assessing the roles and mechanisms of neutrophils in cancer initiation, progression, metastasis and relapse. Although the findings are controversial, the fact that neutrophils play a dual role in promoting and suppressing cancer is undeniable. The plasticity of neutrophils allows them to adapt to different cancer microenvironments and exert different effects on cancer. Given the findings from our own research, we propose a reasonable hypothesis that neutrophils may be reprogrammed into a cancer-promoting state in the cancer microenvironment. This new perspective indicates that neutrophil reprogramming in the course of cancer treatment is a problem worthy of attention. Preventing or reversing the reprogramming of neutrophils may be a potential strategy for adjuvant cancer therapy.

Keywords: Cancer; Cell plasticity; Cell reprogramming; Microenvironment; Neutrophil.

Fig. 1

Dual roles and plasticity of neutrophils in cancer. A Neutrophils with cancer-promoting effects. Neutrophils promote cancer initiation, progression and metastasis: (1) Neutrophils cause DNA damage and gene mutation through ROS produced by MPO, NO produced by iNOS, microRNAs and MMP9, which induce carcinogenesis. (2) Neutrophils eliminate senescence through IL-1RA and thus promote cancer progression. (3) Immunosuppression mediated by the release of Arg-1 from neutrophils to inhibit CD3-mediated T cell activation and proliferation. An acidic pH inhibits the anticancer activity of T cells and NK cells. (4) The acidic pH, cytokines and NETs can increase cancer cell proliferation. (5) Neutrophils promote each step of cancer metastasis. Cytokines released by neutrophils prepare the premetastatic niche in distant organs. MMP9 induces angiogenesis by releasing VEGF from degraded ECM. HMGB1 and TNF promote the migration of cancer cells toward blood vessels. Cathepsin G promotes intravasation through the activation of IGF-1. NETs and the interaction between neutrophils and cancer cells promote cancer cell survival in the peripheral blood. NETs also facilitate extravasation. MMP9 and NE in NETs waken up dormant cancer cells in distant organs causing the formation of metastasis. B Neutrophils with anti-cancer effect. Neutrophils exert a cytotoxic effect via H₂O₂ and NO production induced by MET-mediated iNOS. ADCC during antibody therapy may be another mechanism by which neutrophils kill cancer cells. Chemokines produced by neutrophils recruit T cells and other leukocytes and indirectly kill cancer cells. C Reprogramming between protumor neutrophils and antitumor neutrophils. Generally, in the process of cancer progression, various cytokines released from cancer cells and stromal cells around them may transform anticancer neutrophils into protumor ones. Additionally, many experiments proved that protumor ones or normal neutrophils can be trained to function as anticancer neutrophils. The plasticity of neutrophils has been confirmed based on concrete evidence and should be considered in cancer therapy