Tumor-Associated Macrophages as Target for Antitumor Therapy

Abstract

It is well known that the microenvironment of solid tumors is rich in inflammatory cells that influence tumor growth and development. Macrophages, called tumor-associated macrophages (TAMs), are the most abundant immune cell population present in tumor tissue. Several studies have demonstrated that the density of TAMs is associated with a poor prognosis and positively correlates with tumor growth. Several studies have proved that TAMs may activate and protect tumor stem cells, stimulate their proliferation as well as promote angiogenesis and metastasis. Furthermore, TAMs-derived cytokines and other proteins, such as CCL-17, CCL-22, TGF-β, IL-10, arginase 1, and galectin-3, make a significant contribution to immunosuppression. Since TAMs influence various aspects of cancer progression, there are many attempts to use them as a target for immunotherapy. The numerous studies have shown that the primary tumor growth and the number of metastatic sites can be significantly decreased by decreasing the population of macrophages in tumor tissue, for example, by blocking recruitment of monocytes or eliminating TAMs already present in the tumor tissue. Moreover, there are attempts at reprogramming TAMs into proinflammatory M1 macrophages or neutralizing the protumoral products of TAMs. Another approach uses TAMs for anticancer drug delivery into the tumor environment. In this review, we would like to summarize the clinical and preclinical trials that were focused on macrophages as a target for anticancer therapies.

Cellular metabolism of tumor‐associated macrophages – functional impact and consequences

“…As M2‐like TAMs highly stimulate tumor progression, targeting TAM polarization is an interesting potential therapeutic strategy. Several strategies have been proposed to reprogram TAMs toward M1 macrophages: antibody‐mediated activation of costimulatory CD40, blocking of IL‐10, or targeting intracellular signaling molecules . A novel approach to reprogram macrophages is using histone acetyl deacetylase (HDAC) inhibitors, which cause changes in the transcriptional profile of the macrophages and limits tumor growth .…”

“…A novel approach to reprogram macrophages is using histone acetyl deacetylase (HDAC) inhibitors, which cause changes in the transcriptional profile of the macrophages and limits tumor growth . A comprehensive overview of studies performed targeting TAMs for antitumor therapy has recently been provided in a review by Sawa‐Wejksza and Kandefer‐Szerszen . Since macrophage metabolism is strongly connected to its functionality, metabolic reprogramming of macrophages might be an elegant way to skew the polarization of TAMs toward an antitumor phenotype.…”

Induction of Pro-Inflammatory Response via Activated Macrophage-Mediated NF-κB and STAT3 Pathways in Gastric Cancer Cells

“…Numerous studies have demonstrated that the density of TAMs is associated with a poor prognosis and enhanced tumour growth [11,31,32]. Furthermore, TAM-derived cytokines, such as IL-6, IL-1, IL-8, TNF-α, CCL-17 and CCL-22, significantly contribute to proliferation, immunosuppression, and angiogenesis in support of tumour growth and metastasis [32].…”

“…Macrophages, especially so-called tumour-associated macrophages (TAMs), are the most abundant immune cell population present in tumour tissues, and they are usually marked by CD68 [11,12]. The polarization of macrophages into tumour-suppressive M1 or tumour-promoting M2 types is a fundamental event in the establishment of the tumour microenvironment, and ample evidence has indicated that TAMs are primarily M2 polarized, which act as pro-tumourous factors in many types of human tumours [13,14].…”

Progress on Modulating Tumor‐Associated Macrophages with Biomaterials

“…Current macrophage‐targeted therapies under development aim to: 1) inhibit monocyte/macrophage recruitment, 2) deplete macrophages, or 3) activate macrophage anti‐tumor functions ( Figure and Table 1 ). There exists some controversy about whether TAMs are derived from blood‐circulating monocytes or from infiltrating peripheral tissue macrophages . However, inhibiting monocyte recruitment and their subsequent maturation into TAMs by blocking the C‐C motif chemokine ligand 2 (CCL2)–C‐C motif chemokine receptor 2 (CCR2) axis has indeed improved survival in tumor‐bearing mice .…”