Tumor-associated macrophages as major players in the tumor microenvironment

Abstract

During tumor progression, circulating monocytes and macrophages are actively recruited into tumors where they alter the tumor microenvironment to accelerate tumor progression. Macrophages shift their functional phenotypes in response to various microenvironmental signals generated from tumor and stromal cells. Based on their function, macrophages are divided broadly into two categories: classical M1 and alternative M2 macrophages. The M1 macrophage is involved in the inflammatory response, pathogen clearance, and antitumor immunity. In contrast, the M2 macrophage influences an anti-inflammatory response, wound healing, and pro-tumorigenic properties. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized macrophages and are critical modulators of the tumor microenvironment. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. Consistent with that evidence, experimental and animal studies have supported the notion that TAMs can provide a favorable microenvironment to promote tumor development and progression. In this review article, we present an overview of mechanisms responsible for TAM recruitment and highlight the roles of TAMs in the regulation of tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, we discuss TAM-targeting therapy as a promising novel strategy for an indirect cancer therapy.

Figure 1

Macrophage polarization and its function. Tissue macrophages are derived from circulating monocyte and acquire either a classical M1 or alternative M2 phenotype depending on microenvironmental stimuli. M1 phenotype is driven by IFN-γ and LPS, and produce high levels of the pro-inflammatory cytokines such as IL-6, IL-12, IL-23, and TNF-α. M2 phenotype can be subdivided into M2a, M2b, M2c, and M2d according to different stimuli. M2 macrophages generally produced a high level of IL-10 and demonstrated with high levels of scavenger receptor, mannose receptor, IL-1 receptor antagonist, and IL-1 decoy receptor. M1 phenotype drives pro-inflammatory, cytotoxic and antitumor responses. In contrast, M2 phenotype promotes angiogenesis, immunosuppression, and tumor progression. LPS indicates lipopolysaccharide; IC, immune complex; GC, glucocorticoid; SR, scavenger receptor; MR, mannose receptor; IL-1ra, IL-1 receptor antagonist; TLR, Toll-like receptor; MHC, major histocompatibility complex.

Figure 2

Mechanisms underlying the recruitment of monocytes/macrophages into tumors. Circulating monocytes and tissue-resident macrophages are mobilized into the tumor in response to multiple microenvironmental cues such as cytokines, chemokines, ECM components, and hypoxia. Hypoxic areas release higher amount of chemoattractants such as EMAPII, endothelin, and VEGF-A that enhance macrophage migration to these hypoxic sites. Hypoxia also restrains macrophages by decreasing their mobility through the upregulation of MKP-1 enzymes; this terminates the macrophage response to chemoattractants outside the hypoxic areas.

Figure 3

TAMs support the dissemination of tumor cells from primary to secondary sites. Metastatic processes begin with the invasion of tumor cells through the surrounding ECM, intravasation into the circulation, extravasation, and colonization at secondary sites. TAMs modulate the tumor microenvironment to allow tumor cell invasion by secreting growth factors and proteolytic enzymes. Remodeling of distant microenvironments can be induced by tumor-derived factors prior to the colonization of primary tumor cells. These factors stimulate local macrophages and endothelial cells to promote the recruitment of Mac1⁺ myeloid cells. Mac1⁺ myeloid cells are involved in increased ECM remodeling and pre-metastatic niche formation to allow metastatic tumor colonization. After the successful seeding of tumor cells at secondary sites, recruitment of macrophages and stromal cells are required to support the metastatic outgrowth.

Figure 4

TAMs induce immune dysfunction and enhance tumor progression. Immune system promotes the elimination of tumor by the function of CD8⁺ T cell, NK cell, and M1 macrophage. These immune responses are modulated or suppressed by the tumor microenvironment to allow tumor cells survival. The inefficacy of immune cells to destroy tumor is regulated by TAMs. TAMs support the immunosuppression in tumor by secreting several factors such as CCL22, IL-10, and TGF-β. Treg recruitment into tumor is controlled by the CCL22/CCR4 axis. These cells suppress immune surveillance through multiple mechanisms including inhibition of T cell proliferation and activation or inhibition of NK cell cytotoxicity. Releasing of immunosuppressive factors such as IL-10 and TGF-β can also polarize M1 to M2 macrophage. TAMs also directly inhibit T cell proliferation and cytotoxicity by the PD-L1/PD1 signaling axis.