The Role of Macrophages in Cancer Development and Therapy

Abstract

Macrophages are critical mediators of tissue homeostasis and influence various aspects of immunity. Tumor-associated macrophages are one of the main cellular components of the tumor microenvironment. Depending on their activation status, macrophages can exert a dual influence on tumorigenesis by either antagonizing the cytotoxic activity of immune cells or, less frequently, by enhancing antitumor responses. In most situations, TAMs suppress T cell recruitment and function or regulate other aspects of tumor immunity. The importance of TAMs targeting in cancer therapy is derived from the strong association between the high infiltration of TAMs in the tumor tissue with poor patient prognosis. Several macrophage-targeting approaches in anticancer therapy are developed, including TAM depletion, inhibition of new TAM differentiation, or re-education of TAM activation for cancer cell phagocytosis. In this review, we will describe the role of TAMs in tumor development, including such aspects as protumorigenic inflammation, immune suppression, neoangiogenesis, and enhancement of tissue invasion and distant metastasis. Furthermore, we will discuss therapeutic approaches that aim to deplete TAMs or, on the contrary, re-educate TAMs for cancer cell phagocytosis and antitumor immunity.

Concomitant High Apoptosis Inhibitor of Macrophage (AIM) and Low Prostate-Specific Antigen (PSA) Indicates Activated T Cell-Mediated Anticancer Immunity, Enhance Sensitivity to Pembrolizumab, and Elicit Good Prognosis in Prostate Cancer

“…A recent review of about 300 studies on the prognostic implication of infiltrated M1 or M2 macrophage subtypes, concluded that while the M2 macrophages are associated with poor prognosis, the presence of the M1 macrophages corresponds with a favorable clinical outcome [ 30 ]. It is conceivable that by enhancing the recruitment of CD206 + CD163 + M2 macrophages, PSA facilitates an immunosuppressive TME characterized by upregulated Treg and suppressed dendritic cell pooling, extracellular matrix remodeling, and upregulation of “don’t eat me” signals [ 31 ]. Conversely, we posit that AIM, by enhancing the infiltration of CD80 + CD86 + M1 macrophages, activates adaptive immunity, enhances antigen presentation, represses the “don’t eat me” signal, and thus, reactivates anticancer immune activity [ 30 , 31 ].…”

“…It is conceivable that by enhancing the recruitment of CD206 + CD163 + M2 macrophages, PSA facilitates an immunosuppressive TME characterized by upregulated Treg and suppressed dendritic cell pooling, extracellular matrix remodeling, and upregulation of “don’t eat me” signals [ 31 ]. Conversely, we posit that AIM, by enhancing the infiltration of CD80 + CD86 + M1 macrophages, activates adaptive immunity, enhances antigen presentation, represses the “don’t eat me” signal, and thus, reactivates anticancer immune activity [ 30 , 31 ]. This would be consistent with the concomitant expression of AIM with FCGR2A, FCGR1A, ITGAM, and FCGR3A, all of which play essential roles in enhanced anticancer immune responses and are associated with good clinical outcomes [ 32 , 33 , 34 , 35 ].…”

Pancreatic Cancer Small Extracellular Vesicles (Exosomes): A Tale of Short- and Long-Distance Communication

“…TAMs are critical components of the TME [ 116 ]. Macrophages are involved in numerous biological processes including tissue homeostasis, defense against pathogens and wound healing [ 117 , 118 ]. They originate from circulating monocytes and are transformed at sites of inflammation into activated M1 or M2 phenotypes.…”

Metabolic Hormones Modulate Macrophage Inflammatory Responses

“…Macrophages can be highly influential on tumour development through the induction of inflammation, stimulation of neoangiogenesis, immune suppression or induction of metastasis. Macrophages that populate a tumour’s surrounding environment (the tumour microenvironment (TME)) are referred to as tumour-associated macrophages (TAMs); we direct the reader to the very recent review by Cendrowicz et al [ 11 ] for a detailed description of the contribution of TAMs to the formation and development of tumours. Both clinical and experimental evidence has found that a high density of TAMs within a TME is strongly correlated with poor prognosis and reduced survival in a number of cancer types [ 12 ].…”