Immunotherapy Targeting Tumor-Associated Macrophages

Abstract

Macrophages are phagocytic cells that play a broad role in maintaining body homeostasis and defense against foreign pathogens; whereas tumor-associated macrophages (TAMs) support tumor growth and metastasis by promoting cancer cell proliferation and invasion, immunosuppression, and angiogenesis, which is closely related to the poor prognosis in almost all solid tumors. Hence, deep-insight knowledge into TAMs can provide an opportunity to discover more effective strategies for cancer therapeutics. So far, a large number of therapeutic agents targeting TAMs are in clinical trials. In this review, we introduce an extensive overview about macrophages and macrophage-targeting agents.

Keywords: cancer; immunotherapy; macrophage; polarization; tumor microenvironment.

Figure 1

Origins and polarization of macrophages. (A) Macrophages can have three different developmental pathways: fetal yolk sac, fetal liver, and bone marrow. Precursors seed different tissues and differentiate into specialized tissue-resident macrophages on the basis of tissue-specific context, and they have dramatical differences in their phenotypes and functions. In tumors, TAMs are usually thought to primarily derive from circulating monocytes. (B) According to activation methods, macrophages are divided into M1 and M2 macrophages. M1 macrophages are polarized by LPS, which binds to TLR4. M2a macrophages are induced by IL-4 and IL-13. M2b macrophages are polarized by immune complexes and some TLR ligands. M2c macrophages would increase in the presence of IL-10 or glucocorticoids. M2d macrophages are induced by TLR agonists and adenosine. They have significant differences in surface receptor expression, metabolism, cytokine, and chemokine production. CD169⁺ macrophages, TCRαβ⁺, and TCRγδ⁺ macrophages are classified into neither M1 macrophages nor M2 macrophages.

Figure 2

Targeting TAM strategies in cancer treatments. Several critical targets have been identified that regulate TAMs recruitment, polarization, survival, and phagocytosis during tumor progression. Targeting key receptors or signaling molecules can modulate these macrophage properties and suppress tumor progression. For example, targeting CSF1R can suppress the survival of TAMs. Agonists of CD40 can promote TAMs toward a proinflammatory phenotype that can suppress tumor. Inhibitors of CCR2 or CXCL2 can inhibit monocyte recruitment. Targeting CD47 on tumor cells can promote macrophage phagocytosis of tumor cells. These therapeutic strategies are developed to promote effective antitumor immune responses and many drug candidates are currently investigated in clinical trials for cancer therapy.