Getting TANned: How the tumor microenvironment drives neutrophil recruitment

Abstract

The directed migration of neutrophils to sites of injury or infection is mediated by complex networks of chemoattractant-receptor signaling cascades. The recent appreciation of neutrophils as active participants in tumor progression and metastasis has drawn attention to a number of chemokine-receptor systems that may drive their recruitment to tumors. However, the dynamic nature of the tumor microenvironment (TME) along with the phenotypic diversity among tumor-associated neutrophils (TANs) call for a more comprehensive approach to understand neutrophil trafficking to tumors. Here, we review recent advances in understanding how guidance cues underlie neutrophil migration to primary and secondary tumor sites. We also discuss how the presence of other myeloid cells, such as functionally diverse subsets of tumor-associated macrophages (TAMs), can further influence neutrophil accumulation in tumors. Finally, we highlight the importance of hypoxia sensing in localizing TAMs and TANs in the tumor niche and provide a cohesive view on how both myeloid cell types shape TME-associated extracellular matrix organization, which in turn contribute to tumor progression.

Keywords: cancer; chemokines; chemotaxis; leukocyte tumor interactions; monocytes/macrophages; neutrophils; signal transduction; signaling cascade.

Figure 1. Cartoon depicting the role of chemotactic signaling during the recruitment of neutrophils to the TME

A schematic drawing showing the various mechanisms potentially involved in the recruitment of neutrophils to primary and metastatic tumor sites. (1) Tumor-derived soluble factors (e.g, G-CSF) induce the expansion and mobilization of neutrophils from the bone marrow into the circulation. (2) Immature and (3) mature neutrophils migrate towards tumor sites following gradients of chemokine(s) produced by tumor cells or tumor associated CAFs. Location of recruited neutrophils in peri-tumoral (4), intra-tumoral (5) or stromal (6) regions of the TME. (7) Neutrophils release MMPs, which mediate ECM lysis and release of PGP fragments. (8) Chemotactic PGP peptides amplify neutrophil recruitment. (9) Recruited neutrophils contribute to desmoplasia. (10) Chemokines derived from epithelial cells at distant sites recruit neutrophils, which precede metastatic tumor cells and form a pre-metastatic niche. (11) Tumor cells intravasate into the circulation. (12) Neutrophil-derived NETs trap circulating tumor cells. (13) Neutrophil-derived IL-8 enhances extravasation of tumor cells. (14) Cancer cell-derived factors (e.g, G-CSF) induce neutrophils to release NETs (15), which in turn promote cancer cell migration and colonization in distant tissues.

Figure 1. Cartoon depicting the role of chemotactic signaling during the recruitment of neutrophils to the TME

A schematic drawing showing the various mechanisms potentially involved in the recruitment of neutrophils to primary and metastatic tumor sites. (1) Tumor-derived soluble factors (e.g, G-CSF) induce the expansion and mobilization of neutrophils from the bone marrow into the circulation. (2) Immature and (3) mature neutrophils migrate towards tumor sites following gradients of chemokine(s) produced by tumor cells or tumor associated CAFs. Location of recruited neutrophils in peri-tumoral (4), intra-tumoral (5) or stromal (6) regions of the TME. (7) Neutrophils release MMPs, which mediate ECM lysis and release of PGP fragments. (8) Chemotactic PGP peptides amplify neutrophil recruitment. (9) Recruited neutrophils contribute to desmoplasia. (10) Chemokines derived from epithelial cells at distant sites recruit neutrophils, which precede metastatic tumor cells and form a pre-metastatic niche. (11) Tumor cells intravasate into the circulation. (12) Neutrophil-derived NETs trap circulating tumor cells. (13) Neutrophil-derived IL-8 enhances extravasation of tumor cells. (14) Cancer cell-derived factors (e.g, G-CSF) induce neutrophils to release NETs (15), which in turn promote cancer cell migration and colonization in distant tissues.