Although there is some debate, most evidence suggests that TAMs have a tumor-promoting phenotype. TAMs affect most aspects of tumor cell biology and drive pathological phenomena including tumor cell proliferation, tumor angiogenesis, invasion and
metastasis, immunosuppression, and drug resistance.
Angiogenesis Tumor
angiogenesis is the process by which a tumor forms new blood vessels in order to maintain a supply of nutrients and oxygen and to grow beyond a few millimeters in size. The formation of vasculature also facilitates the escape of malignant cells into blood circulation and the onset of metastasis. One of the primary tumor-promoting mechanisms of TAMs is the secretion of potent pro-angiogenic factors. The most highly expressed and well-characterized angiogenic factor produced by TAMs is
vascular endothelial growth factor A (VEGF-A). TAMs accumulate in hypoxic regions of the tumor, which induces the expression of
hypoxia-inducible factors (HIF-1) that regulate VEGF expression. In addition to producing VEGF-A, TAMs have been shown to modulate VEGF-A concentration through
matrix metalloproteinase (MMP)-9 activity and by producing
WNT7B that induces endothelial cells to produce VEGF-A. In addition to VEGF-A, TAMs secrete the pro-angiogenic factors
tumor necrosis factor α (TNF-α),
basic fibroblast growth factor,
urokinase-type plasminogen activator,
adrenomedullin, and
semaphorin 4D. Tie2+ TAMs associate with blood vessels through
angiopoietin-2 produced by endothelial cells and activate angiogenesis through
paracrine signaling. When angiopoietin-2 is bound, these TAMs upregulate expression of more angiogenic factors, such as
thymidine phosphorylase and
cathepsin B. Angiopoietin-2 also causes Tie2+ TAMs to express T-cell regulating factors
interleukin (IL)-10 and
chemokine (C-C motif) ligand (CCL) 17; these factors limit T-cell proliferation and upregulate expansion of regulatory T cells, allowing tumor cells to evade immune responses. Tumor
lymphangiogenesis is closely related to tumor angiogenesis, and there is substantial evidence that factors produced by TAMs, especially those of the VEGF family and their receptor tyrosine kinases, are responsible for this link. In low-oxygen regions of a solid tumor, mononuclear
myeloid-derived suppressor cells (M-MDSC) quickly turn into tumor-associated macrophages. Additionally, the
crosstalk between M-MDSCs and other macrophages enhance the protumor activities of TAMs.
Immune suppression One of the major functions of TAMs is suppressing the T-cell mediated anti-tumor immune response. Gene expression analysis of mouse models of breast cancer and fibrosarcoma shows that TAMs have immunosuppressive transcriptional profiles and express factors including IL-10 and
transforming growth factor β (TGFβ). In humans, TAMs have been shown to directly suppress T cell function or even cause their direct cell death through surface presentation of
programmed death-ligand 1 (PD-L1) in hepatocellular carcinoma or glioblastoma and B7-homologs in ovarian carcinoma, which activate
programmed cell death protein 1 (PD-1) and
cytotoxic T-lymphocyte antigen 4 (CTLA-4), respectively, on T cells. In both mouse and humans, TAMs co-expressing T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and V-domain Ig suppressor of T cell activation (VISTA) have been shown to promote immunotherapy-resistance and inhibit immunogenic cell death (ICD). Inhibitory signals to PD-1 and CTLA-4 are immune checkpoints, and binding of these inhibitory receptors by their ligands prevents T cell receptor signaling, inhibits T cells cytotoxic function, and promotes T cell apoptosis. HIF-1α also induces TAMs to suppress T cell function through arginase-1, but the mechanism by which this occurs is not yet fully understood. Recently, Siglec-15 has also been identified as an immune suppressive molecule that is solely expressed on TAMs, and could be a potential therapeutic target for cancer immunotherapy. ==Subtypes==