Macrophages Associated with Tumors as Potential Targets and Therapeutic Intermediates

Abstract

Tumor-associated macrophages (TAMs) form approximately 50% of tumor mass. TAMs were shown to promote tumor growth by suppressing immunocompetent cells, inducing neovascularization and supporting cancer stem cells. TAMs retain mobility in tumor mass, which can potentially be employed for better intratumoral biodistribution of nanocarriers and effective tumor growth inhibition. Due to the importance of TAMs, they are increasingly becoming principal targets of novel therapeutic approaches. In this review, we compare features of macrophages and TAMs that are essential for TAM-directed therapies, and illustrate the advantages of nanomedicine that are related to the preferential capture of nanocarriers by Mφ in the process of drug delivery. We discuss recent efforts in reprogramming or inhibiting tumor-protecting properties of TAMs, and potential strategies to increase efficacy of conventional chemotherapy by combining with macrophage-associated delivery of nanodrugs.

TAM macrophages promote growth and metastasis within the cancer ecosystem

“…[4][5][6][7] These cells are an essential cellular component of the innate immune system and are derived from myeloid progenitor cells in the bone marrow compartment. These progenitor cells develop into promonocytes and are released into the circulation where they undergo differentiation into monocytes.…”

“…These monocytes then migrate into tissues where they differentiate into resident tissue macrophages and help to protect these sites from infection and injury as activated ("M1") or alternatively activated macrophages ("M2"). [4][5][6][7] In addition to this role in innate immunity, recent evidence suggests that macrophages also play an important role in the regulation of angiogenesis in both normal and diseased tissues, including malignant tumors. [4][5][6][7] It is not clear whether TAMs are derived from peripheral blood monocytes recruited into the tumor from the circulation or from resident macrophages already in the healthy tissue before tumor develops and metastasizes.…”

“…[4][5][6][7] In addition to this role in innate immunity, recent evidence suggests that macrophages also play an important role in the regulation of angiogenesis in both normal and diseased tissues, including malignant tumors. [4][5][6][7] It is not clear whether TAMs are derived from peripheral blood monocytes recruited into the tumor from the circulation or from resident macrophages already in the healthy tissue before tumor develops and metastasizes. Elevated expression of a number of monocyte chemoattractants, including chemokine (C-C motif) ligand 2 (CCL2), CCL3, CCL4, CCL8 and CCL5 (RANTES) by both tumor and stromal cells within tumors has been shown to positively correlate with increased number of TAMs in many human tumors.…”

Mannose-coated gadolinium liposomes for improved magnetic resonance imaging in acute pancreatitis

“…11 This phagocytic property can be utilized to target macrophages using nanoparticles. 12 Nanoparticles that are used as imaging agents, such as superparamagnetic iron oxide particles (SPIO) or ultra SPIO, take advantage of the fact that they are predominantly internalized by macrophages and induce a change in the signal intensity of magnetic resonance imaging (MRI). 13,14 These imaging agents have been widely used in many macrophage-associated diseases, such as myocardial inflammation, atherosclerosis, and liver tumors.…”

Nanoparticle design to induce tumor immunity and challenge the suppressive tumor microenvironment

“…Most importantly, they protect tumor cells from chemotherapeutics, attract T regs and induce CTL apoptosis. To deal with TAMs, there are 3 main options, which are summarized in Figure 5 [115,116]. Firstly, the infiltration of inflammatory monocytes and their differentiation into M2 polarized macrophages could be inhibited.…”