Priming of neutrophils toward NETosis promotes tumor growth

Abstract

Neutrophils play a major role in cancer biology and both pro-and antitumoral functions of tumorinfiltrating neutrophils have been described. We have shown that tumors, by releasing G-CSF into the bloodstream, prime circulating neutrophils to form neutrophil extracellular traps (NETs) and we have detected the presence of NETs within the tumor microenvironment. Here, we report, using PAD4-deficient mice with a defect in neutrophil chromatin decondensation and NET formation, that the priming of neutrophils toward NETosis favors tumor growth. Interestingly, in a tumor model that does not release G-CSF and in which neutrophils are not primed for NETosis, PAD4-deficiency did not reduce tumor growth. However, supplying exogenous G-CSF to the wild-type (WT) host promoted intratumoral NETosis and tumor growth. Taken together, our results suggest that the priming of neutrophils for NETosis by the tumor or its environment leads to the accumulation of intratumoral NETs and a growth advantage to the tumor. Our work unveiled a pro-tumoral role for NETs which strengthens their potential as a new target in the fight against cancer.

Neutrophils, G‐CSF and their contribution to breast cancer metastasis

“…Similarly, neutrophils from naïve mice treated with recombinant G‐CSF were predisposed to NET formation when stimulated with platelet activating factor ex vivo . Although this study mechanistically recognized NETs as driving a pro‐thrombotic state in the lungs of tumour‐bearing mice, the authors later demonstrated that NETs have a role in tumour growth . Interestingly, the latter study indicated that tumour‐derived levels of G‐CSF dictated the ability of tumour‐infiltrating neutrophils to form NETs, linking their formation to a specific neutrophil phenotype (CD11b high ) that was found in high‐G‐CSF‐secreting tumours .…”

Infiltrating Myeloid Cells Exert Protumorigenic Actions via Neutrophil Elastase

“…Therefore, NE may be localized to several different compartments – intracellular (granular, and even nuclear) or extracellular, consistent with the staining seen in Fig 7 and Supplementary Fig 2. Cancer cells secrete factors that predispose granulocytes to undergo NETosis, leading to enhanced primary tumor growth, metastatic initiation and colonization, and cancer-associated morbidities like thrombosis and end organ damage (21–23). Indeed, prostate cancer patients have elevated plasma concentrations of G-CSF and IL8, two factors that likely prime circulating and infiltrating granulocytic MDSCs for NETosis (24, 27).…”

“…NETs are externalized protease-laden DNA fibers released upon neutrophil activation in response to infection or cancer burden (20). NETs play an important role in cancer pathology, promoting primary tumor growth and development of a metastatic niche (21–23). In the context of prostate cancer, tumor-derived cytokines like IL8 have been shown to attract myeloid-derived suppressor cells (MDSCs) and elicit extrusion of NETs within the tumor microenvironment (24).…”

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

“…This was related to their sheer numbers, as circulating pDC were 27 times more efficient in secreting IFN-α, but PMN were 100 times more frequent (289). Second, both T1-IFNs and IL-17-induced G-CSF prime PMN for NETosis (250, 290). In accord, circulating PMN of SLE patients are also the main cells expressing the transcriptional T1-IFN signature and release more NETs than PMN from healthy individuals (250, 253, 288, 289, 291, 292).…”