Heterogeneity of neutrophils in cancer: one size does not fit all

Neutrophils have protumor properties including causing DNA damage, and promoting tumor proliferation, angiogenesis, and immunosuppression. (A) Neutrophils cause DNA instability through genotoxic DNA substances including ROS, NOS, iNOS, and microRNAs such as miR-23a and miR-155, thus leading to tumor initiation and progression in multiple models (see text). (B) In a PTEN null prostate tumor model, neutrophils promote the proliferation of cancer cells by counteracting senescence with IL1RA production; anaplastic thyroid cancer conditioned medium induces TANs to release NETs in a mitochondrial DNA dependent manner, thereby promoting tumor proliferation. In a RAS-derived neoplasia zebrafish model, neutrophils produce PGE2, thus promoting proliferation of the pre-neoplastic cells in wounded tail fins. In a RAS-induced lung cancer model, neutrophil NE directly induces tumor cell proliferation by infiltrating into the endosomal compartment, degrading IRS-1, and activating PI3K signaling within tumor cells. (C) Neutrophils facilitate tumor angiogenesis via releasing MMP9 and BV8 in a transgenic mouse model with pancreatic islet cell carcinogenesis. (D) Immunosuppressive functions of neutrophils. Neutrophils produce Arg1, ROS, and iNOS, thus impairing the T cell-mediated anti-tumor response. In human hepatocellular carcinomas and gastric cancers, PD-L1⁺ neutrophils hinder the proliferation and activation of T cells, thus leading to the proliferation and progression of cancer cells. In a melanoma mouse model, VISTA expressed on neutrophils negatively regulates T cell-mediated antitumor immunity; NETs released in the TME form a protective layer on tumor cells and shield them from the cytotoxic activity of CD8⁺ T cells and NK cells. In a non-alcoholic steatohepatitis-hepatocellular carcinoma (NASH-HCC) model, tumor-induced NETs positively correlate with promotion of Treg differentiation in cancer by metabolic reprogramming of naïve CD4⁺ T-cells, thereby bolstering hepatocarcinogenesis.

Neutrophils have direct and indirect antitumor effects. (A) Neutrophils directly kill tumor cells through the production of H₂O₂, in a process involving TRPM2, an H₂O₂-dependent channel, thus causing lethal influx of Ca2⁺ into breast cancer cells. In Lewis lung carcinoma and fibrosarcoma transplantation mouse models, tumor-derived TNFα induces MET expression on neutrophils, which then interact with HGF and promote the production and release of NO by neutrophils, thus killing tumor cells. In cytotoxic assays of neutrophils against the Jurkat human T cell leukemic cell line, neutrophils express TRAIL on the cell surfaces and release it into the culture medium, thus increasing leukemia cell apoptosis. Arg1 derived from activated neutrophils or dead cells has been shown to induce apoptosis of the HeLa human cervical epithelial carcinoma cell line as well as the SF268 human glioblastoma cell line through activation of the ER stress pathway. Neutrophils kill cancer cells and attenuate tumorigenesis through releasing catalytically active NE, which proteolytically liberates the CD95 death domain (DD) and leads to breast cancer cell apoptosis. (B) In 3-methylcholathrene (3-MCA)-induced sarcomagenesis, neutrophils increase the production and release of IL-12 in macrophages, thereby promoting the polarization and IFN-γ production in a subset of CD4^-CD8^-TCRβ⁺ unconventional T cells and exerting an anti-tumor response. Cross-talk between N1 TANs and activated CD4⁺ and CD8⁺ T cells induces the expression of costimulatory molecules such as CD54, CD86, OX40 L, and 4-1BBL on the neutrophil surface, which in turn promote T cell activation and INF-γ production. (C) Neutrophils directly kill breast cancer target cells via Fc-mediated destruction of the cancer cell plasma membrane (trogoptosis). Destruction of antibody-opsonized cancer cells mediated by neutrophils is enhanced by blocking the CD47-SIRPα do not-eat-me checkpoint.