Context Drives Diversification of Monocytes and Neutrophils in Orchestrating the Tumor Microenvironment

Abstract

Recent preclinical/clinical studies have underscored the significant impact of tumor microenvironment (TME) on tumor progression in diverse scenarios. Highly heterogeneous and complex, the tumor microenvironment is composed of malignant cancer cells and non-malignant cells including endothelial cells, fibroblasts, and diverse immune cells. Since immune compartments play pivotal roles in regulating tumor progression via various mechanisms, understanding of their multifaceted functions is crucial to developing effective cancer therapies. While roles of lymphoid cells in tumors have been systematically studied for a long time, the complex functions of myeloid cells have been relatively underexplored. However, constant findings on tumor-associated myeloid cells are drawing attention, highlighting the primary effects of innate immune cells such as monocytes and neutrophils in disease progression. This review focuses on hitherto identified contextual developments and functions of monocytes and neutrophils with a special interest in solid tumors. Moreover, ongoing clinical applications are discussed at the end of the review.

Keywords: cancer immunology; innate immunity; monocytes; myeloid cell heterogeneity; neutrophils; tumor microenvironment.

Figure 1

Monocytes mediate a variety of pro-tumoral and anti-tumoral mechanisms in a context-dependent way. In primary tumors, Ly6C^hi monocytes exert pro-tumoral effects to promote cancer cell proliferation and cancer cell intravasation. Of note, anti-angiogenic therapy induces Ly6C^lo monocyte-mediated immunosuppressive tumor microenvironment and triggers resistance against the therapy. Under the treatment, non-classical Ly6C^lo monocytes have been revealed to extravasate to primary tumor regions. The tumor-infiltrated Ly6C^lo monocytes significantly contribute to inhibition of cytotoxic T cell function. In metastatic niches, Ly6C^hi monocytes and Ly6C^lo monocytes facilitate cancer cell extravasation by secreting pro-angiogenic molecules and by mediating the release of ECM-bounded VEGF molecules. In contrast, these monocytes display anti-tumoral functions in different settings. In the lung metastatic sites, Ly6C^lo monocytes recruit tumor-killing NK cells, and scavenge tumor materials in the lung vasculature. Meanwhile, Ly6C^hi monocytes degrade fibrosis around cancer cells, which have the cancer cells acquire chemosensitivity upon treatments.

Figure 2

Neutrophils differentially regulate tumor microenvironment with diverse mechanisms. Neutrophils perform pro-tumoral roles in most tumor settings, promoting tumorigenesis, and cancer cell proliferation via diverse mechanisms. Moreover, neutrophils regulate the functions of other immune cells including cytotoxic T cells and Tregs in order to build up tumor-favorable tumor microenvironment. On the one hand, neutrophils stimulate tumor angiogenesis via inducing the release of VEGF and FGF-2 from ECM or secreting pro-angiogenic molecules, themselves. Furthermore, metastatic competence of cancer cells can be achieved by physical interaction with neutrophils and neutrophil-derived secretory molecules, facilitated to extravasate to secondary tumor sites. Neutrophils also create a positive feedback loop with cancer cells toward the formation of the tumor-supportive microenvironment, developing dysfunctional vasculature around the tumor, leading to hypoxia which recruits more neutrophils and pro-tumoral immune cells into tumor milieu. On the other hand, a couple of studies indicate anti-tumoral functions of neutrophils in different contexts. In these contexts, neutrophils perform a cytotoxic function on cancer cells, and have cancer cells lose proliferative and metastatic properties.