Tumor-associated neutrophils display a distinct N1 profile following TGFβ modulation: A transcriptomics analysis of pro- vs. antitumor TANs

Abstract

It is becoming increasingly clear that tumor-associated neutrophils (TANs) play an important role in cancer biology, through direct impact on tumor growth and by recruitment of other cells types into the tumor. The function of neutrophils in cancer has been the subject of seemingly contradicting reports, pointing toward a dual role played by TANs in tumor progression. The existence of multiple neutrophil subsets, as well as phenotypic modulation of the neutrophils by various factors in the tumor microenvironment, has been shown. TGFb plays a significant role in the determination of neutrophils' phenotype, by shifting the balance from an antitumor (N1) toward a more permissive (N2) phenotype. The full range of mechanisms responsible for the pro-vs. antitumor effects of TANs has not yet been elucidated. Therefore, the ability to identify the different neutrophil subpopulations in the tumor is critical in order to understand TANs evolution and contribution throughout tumor progression. Using a transcriptomic approach, we identified alternations in gene expression profile following TGFb inhibition. We show that N1 and N2 TANs represent distinct subpopulations with different transcriptional signatures and both differ from naive bone marrow neutrophils. The analysis highlights a clear difference in pathways involved in neutrophil function such as cytoskeletal organization and antigen presentation, as well as alterations in chemokine profile, eventually affecting their effect on tumor cells and tumor growth. These data highlights several potential new pathways and mechanisms by which neutrophils can influence both the tumor cells and the adaptive immune system.

Cancer‐related circulating and tumor‐associated neutrophils – subtypes, sources and function

“…In their review on TANs as targets for cancer therapy , Gregory and Houghton raised the interesting question whether the differences between N1 and N2 TANs were due to two unique transcriptional programs as suggested in our work or instead represented two states of activation, that is, that N1 TANs produce the same mediators, but at different levels. In our recently published transcriptomic comparison between N1 and N2 TANs, we found that a vast majority of the changes were indeed upregulation of the same genes and pathways in N1 TANs compared to N2 TANs . However, there were some clear exceptions.…”

Barriers to Radiation-Induced In Situ Tumor Vaccination

“…Importantly, aside from their well-described role in host defenses, accumulating evidence indicate that neutrophils exhibit a high phenotypic and functional plasticity depending upon TGFβ available in the TME (117). Indeed, similar to macrophages, TGFβ has been shown to drive the phenotype change of a more tumor cytotoxic and pro-inflammatory phenotype (N1) into a tumor supportive phenotype (N2) (113).…”

Neutrophil recruitment and function in endometriosis patients and a syngeneic murine model

“…Through an extensive time course (24,48, 72 hours, 7, and 28 days) characterization of this model, we observed a significant neutrophil influx within the peritoneal fluid early (24-72 hours) after surgical induction of endometriosis compared to sham-operated controls. Through an extensive time course (24,48, 72 hours, 7, and 28 days) characterization of this model, we observed a significant neutrophil influx within the peritoneal fluid early (24-72 hours) after surgical induction of endometriosis compared to sham-operated controls.…”

“…Through an extensive time course (24,48, 72 hours, 7, and 28 days) characterization of this model, we observed a significant neutrophil influx within the peritoneal fluid early (24-72 hours) after surgical induction of endometriosis compared to sham-operated controls. 18,24,44 Early neutrophil recruitment was associated with elevated peritoneal fluid inflammatory cytokines (TNF-α, IL-6, IL-4), neutrophil chemokines (G-CSF, CXCL1), and the angiogenic growth factor, VEGF, which have been previously associated with endometriosis. Nonetheless, this rapid innate response of neutrophils is seen in various models of sterile tissue injury and repair, and further highlights the potential for refluxed endometrial debris to serve as a mediator of sterile inflammation.…”

“…In addition to their ability to serve as key early responders to tissue injury including menstruation, neutrophils may also promote wound healing and the resolution of inflammation. [22][23][24] These advances have shed light on the potential for neutrophil heterogeneity and plasticity and have dramatically shifted how we consider these innate immune sentinels and their involvement in chronic inflammatory processes. 12,16,17 Not only can the local microenvironment shape the polarization of these cells, such as in the context of tumor-associated neutrophils, but neutrophils may also serve as a prominent source of pro-inflammatory and pro-angiogenic mediators.…”