Macrophages: Key orchestrators of a tumor microenvironment defined by therapeutic resistance

Abstract

Macrophages have emerged as promising therapeutic targets in cancer. Within tumor tissue, macrophages foster tumor development, invasion, and metastasis. As the phenotype of macrophages is inherently pliable and dependent on cues received from the surrounding microenvironment, macrophages co-evolve with malignant and other non-malignant cells during cancer progression. In doing so, they establish a microenvironment that is therapeutically resistant and thwarts the productivity of T cell immunosuveillance. Strategies designed to deplete, inhibit, or redirect macrophages with anti-tumor activity are being explored to reverse the pro-tumor properties of macrophages that are commonly observed in cancer. In this review, we discuss our current understanding of the mechanisms that regulate macrophage recruitment to tumors, their impact on the tumor microenvironment, and their promise as therapeutic targets for improving the efficacy of cytotoxic- and immune-based therapies.

Keywords: Cancer; Chemotherapy; Immunotherapy; Macrophages; Resistance; Tumor.

Figure 1. Origins of tissue resident macrophages

In the steady state, tissue macrophages are either (i) yolk sac- or fetal liver-derived (shown in brown) or (ii) monocyte-derived from the bone marrow (shown in green). Macrophages residing in the brain, liver, lungs, and red pulp of the spleen are predominately derived from the yolk sac with Langerhans cells of the skin derived from fetal liver. In contrast, resident macrophages in the gastrointestinal tract are mainly monocyte-derived. In the setting of inflammation, monocyte-derived macrophages infiltrate tissues and co-exist with tissue resident macrophages.

Figure 2. Targeting macrophage biology in cancer

Macrophages can mediate an array of biological activities in cancer (e.g. chemotaxis, direct cytotoxicity against tumor cells, regulation of fibrosis and vascularity as well as suppression and exclusion of T cells. Multiple molecules are associated with each of these activities and serve as targets for therapeutic intervention involving strategies that inhibit, deplete or redirect macrophages in cancer.

Figure 3. Macrophages regulate therapeutic resistance in cancer

Macrophage phenotype is associated with cancer sensitivity to therapeutic intervention. Tumor promoting macrophages orchestrate a microenvironment that is supportive of tumor resistance. However, the inherent pliability of macrophage phenotype presents an opportunity to shift the polarity of macrophages from tumor-promoting to tumor-suppressing by targeting molecules (e.g. CD40, TLRs, IFN-γ, CD47, HDAC IIa, IL-4, IL-13, and IL-10) involved in regulating macrophage phenotype. Tumor suppressing macrophages can prime malignant cells for increased sensitivity to cytotoxic and immune based therapies as well as modulate the stromal microenvironment for enhanced therapeutic efficacy.