Neutrophils Undergo NETosis to Block Cytotoxic Lymphocytes from Tumors

Neutrophils, often considered to be protumorigenic, produce neutrophil extracellular traps (NET) via a unique form of cell death called NETosis. Although these NETs may be key for entrapping invading microbes, they have been linked to metastasis and poor prognosis in some human cancers. Teijeira and colleagues found that neutrophil chemoattractants, including chemokines that are ligands for the chemokine receptors CXCR1 and CXCR2, which are expressed by neutrophils and the neutrophil-like granulocytic myeloid-derived suppressor cells (GR-MDSC), caused NETosis of neutrophils and GR-MDSCs. Further experiments confirmed that agonists of CXCR1 and CXCR2 were the primary factors responsible for NETosis in tumors, and these agonists, such as IL8, could be derived from tumor cells. In 3-D tumor spheroid cultures, NET formation prevented the antitumor effects of CD8⁺ T cells and natural killer (NK) cells, and this appeared to be because NETs coating the tumor cells impaired the motility of these cytotoxic immune cells and physically blocked them from reaching the tumor cells. Experiments employing intravital microscopy, a technique that enables imaging in live animals, supplied additional evidence that NETs prevent contact between tumor cells and cytotoxic CD8⁺ T cells and NK cells. Illustrating the potential clinical relevance of these findings, in vivo experiments using tumors derived from mouse breast cancer cells showed that preventing NET formation enabled NK cells to restrict lung metastasis. Further, although pharmacologic inhibition of PAD4 (a treatment that blocks NETosis) did not delay progression of established tumors in this model, PAD4 inhibition synergized with combined immune-checkpoint blockade using anti–PD-1 plus anti-CTLA4 in a process dependent on CD8⁺ T cells. Collectively, this work shows that one mechanism by which tumors can evade immunity is to produce chemokines that lure neutrophils, which undergo NETosis to provide a protective coating that shields the tumor cells from antitumor immune cells.

Teijeira Á, Garasa S, Gato M, Alfaro C, Migueliz I, Cirella A, et al. CXCR1 and CXCR2 chemokine receptor agonists produced by tumors induce neutrophil extracellular traps that interfere with immune cytotoxicity. Immunity 2020 Apr 13 [Epub ahead of print].

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