Neutrophils in the tumor microenvironment: trying to heal the wound that cannot heal

Abstract

Neutrophils are the first responders to infection and injury and are critical for antimicrobial host defense. Through the generation of reactive oxidants, activation of granular constituents and neutrophil extracellular traps, neutrophils target microbes and prevent their dissemination. While these pathways are beneficial in the context of trauma and infection, their off-target effects in the context of tumor are variable. Tumor-derived factors have been shown to reprogram the marrow, skewing toward the expansion of myelopoiesis. This can result in stimulation of both neutrophilic leukocytosis and the release of immature granulocytic populations that accumulate in circulation and in the tumor microenvironment. While activated neutrophils have been shown to kill tumor cells, there is growing evidence for neutrophil activation driving tumor progression and metastasis through a number of pathways, including stimulation of thrombosis and angiogenesis, stromal remodeling, and impairment of T cell-dependent anti-tumor immunity. There is also growing appreciation of neutrophil heterogeneity in cancer, with distinct neutrophil populations promoting cancer control or progression. In addition to the effects of tumor on neutrophil responses, anti-neoplastic treatment, including surgery, chemotherapy, and growth factors, can influence neutrophil responses. Future directions for research are expected to result in more mechanistic knowledge of neutrophil biology in the tumor microenvironment that may be exploited as prognostic biomarkers and therapeutic targets.

Keywords: cancer; inflammation; injury; neutrophils; wound repair.

FIGURE 1

The good and bad of wound repair mechanisms. (A) When injury (e.g. traumatic injury or acute infection) occurs, the inflammatory response follows an ordered transition during normal wound healing. The first stage of acute inflammation involves neutrophil and platelet recruitment and activation, followed by chronic inflammation involving M2 macrophage accumulation and T cell suppression. Finally, the injurious stimulus is alleviated (e.g. clearance of infection) and resolution of inflammation occurs. Resolution includes tissue regeneration, which requires growth factors, angiogenesis, and fibrosis. (B) Pathologic wound healing is associated with a persistent and disordered inflammatory response. Examples include persistent diabetic wounds and cancer. In these scenarios, neutrophil activation is ongoing, which drives the rest of the inflammatory pathways and prevents resolution from occurring. In the context of cancer, pathologic wound healing can drive tumor progression through a number of pathways that are concurrently activated, including thrombosis and angiogenesis, matrix remodeling, release of growth factors, and T cell suppression

FIGURE 2

Neutrophils within the tumor microenvironment possess heterogeneity in regard to arginase-1 (Arg-1) expression. Flow cytometric analysis of peripheral blood (A) and ascites (B) from a patient with newly diagnosed ovarian cancer prior to therapy. Blood was collected pre-operatively on the day of surgery, and ascites was collected intra-operatively prior to tumor resection. The upper left panel shows the ungated scatter of all cells within the sample, the upper right panel is the proportion of CD45⁺ cells in the ungated population, the lower left is the proportion of CD15⁺ cells in the ungated population, and the lower right panel shows the CD66b and Arg-1 expression of the CD15⁺ cells. In blood there is a single population of CD15⁺ CD66b⁺ Arg-1⁺ cells, while in ascites two distinct populations were observed: CD15⁺ CD66b⁺ Arg-1 low and CD15⁺ CD66b⁺ Arg-1 intermediate. The difference in Arg-1 expression may relate to differences in transcription or Arg-1 release from activated neutrophils. Neutrophils can be tracked throughout the plots by the purple-colored cells