Macrophages in Cancers
Macrophages in Tumour Microenvironment
The origin, progression and dissemination of solid tumors are strongly regulated by stromal, endothelial or defense-related cells. Tumor cells do not merely grow into an inert interstitial tissue, but they actively interact with their microenvironment establishing cell-to-cell contacts, releasing soluble factors and responding to soluble factors released by neighboring cells. The tumor microenvironment is a complex assembly of genetically heterogeneous cancer cells. Endothelial cells, cancer-associated fibroblasts, and different populations of immune cells comprise the local environment of tumors. Macrophages are one of the most abundant immune cells and there is a strong correlation between the density of macrophages and poor survival in a variety of cancers, including Lung Cancer, Liver Cancer, Glioblastoma, Breast Cancer, Colorectal Cancer, Pancreatic Cancer, and Gastric Cancer. Recently, accumulating evidence supports a dual role for macrophages in the regulation of tumor cell proliferation, invasion, angiogenesis or immune control. On one side, the resident tissue macrophages have a cytotoxic function against tumor development. On the other side, monocyte-derived tumor-associated macrophages (TAMs) show opposite behavior with a commonly protumoral phenotype.
TAM Phenotypes
In response to changes in their immediate environment, macrophages display a high degree of adaptability. They could be polarized into two distinct phenotypes, M1 and M2 phenotypes. The M1 phenotype is associated with the production of proinflammatory cytokines, such as interleukin (IL)-12, interferon γ (IFNγ) and tumor necrosis factor alpha (TNFα), antigen presentation, generation of reactive oxygen species, and the ability to eliminate pathogens and cells. In contrast, the M2 phenotype is associated with the production of anti-inflammatory cytokines, such as IL-10, upregulation of scavenging receptors, and tissue remodeling. TAMs are typically associated with an M2-like polarization state. This state is caused by tumor-derived lactic acid or secretion of immunosuppressive cytokines from different cells in the tumor microenvironment or immunoglobulins for B cells. In colorectal carcinoma, although M2 macrophages outnumber M1, the presence of M1 macrophages is associated with a better prognosis.
Functions of Macrophages in Cancers
By secreting various factors and affecting other immune cells, macrophages not only play a role in chronic inflammation but also initiate, promote, or suppress the development of cancer. Some important factors, such as Ornithine, vascular endothelial growth factor (VEGF), epidermal growth factor (EGF), and transforming growth factor beta (TGFβ), can promote the development of cancer, while nitric oxide generated by inducible nitric oxide synthase in macrophages can inhibit tumor growth. Previous studies have shown that macrophages are involved directly or indirectly in angiogenesis, invasiveness, metastasis, regulation of the tumor microenvironment, and therapeutic resistance.
Fig.1 Functions of macrophages in cancers. (Duan, 2021)
Manipulation of TAMs to Improve Cancer Therapy
Increasing evidence indicates that TAMs may influence the efficacy of anticancer therapies. Therefore, TAM depletion is one choice to manipulate TAMs. For instance, 1) trabectedin, a DNA-damaging agent approved for the treatment of soft tissue carcinomas, may rely on its ability to kill TAMs rather than tumor cells. 2) Trabectedin administration can reduce tumor growth even when drug-resistant carcinomas have been transplanted in immunocompetent mice, an occurrence correlating with reduced TAM density. 3) Docetaxel depletes immunosuppressive TAMs and drives concomitant expansion of antitumor myeloid cells. 4) Since CSF-1/CSF-1R signalings axis is essential for macrophage survival, inhibition of CSF-1/CSF-1R signaling is an effective approach to deplete TAM.
Inhibition of circulating monocyte recruitment into the tumor is an alternative approach to selectively deplete TAMs. As TAM recruitment is CCL2-dependent in most cancer types, this inhibition can be effectively achieved by interfering with CCL2-CCR2 signaling. Studies have shown that antibody-mediated blockade of CCL2 inhibited monocyte recruitment to primary breast tumors and metastatic sites in the lungs, leading to reduced tumor growth and improved survival. However, interruption of anti-CCL2 therapy caused a rapid rebound of monocyte infiltration in tumors, correlating with accelerated metastatic relapse.
Functional reprogramming of TAMs to enhance their antitumor properties while limiting the protumor ones is the most attractive strategy for cancer therapy. TAMs represent the major source of IL-10. Previous studies have shown that the inhibition of IL-10 signaling in a mouse model of mammary carcinoma can significantly improve the efficacy of chemotherapy. Moreover, inhibition of IL-10 signaling closely phenocopied the effects of CSF-1R blockade in the same system, highlighting the possibility of alternative and more targeted therapies directed against the protumor functions of TAMs. The observed therapeutic effects relied at least partially on direct repurposing of TAMs towards immunostimulatory functions, likely including direct activation of NK and T cells by IFNα administration
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References
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Ostuni, R.; et al. Macrophages and cancer: from mechanisms to therapeutic implications. Trends in immunology. 2015, 36(4):229-39.
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Duan, Z.; Luo, Y. Targeting macrophages in cancer immunotherapy. Signal Transduction and Targeted Therapy. 2021, 6(1):1-21.
