Mechanisms of Tumor-Associated Macrophage TAM-Mediated Immunosuppression

Tumor-Associated Macrophage (TAM)-Mediated Mechanisms of Immunosuppression

Tumor-associated macrophages (TAMs) are a heterogeneous population of cells that display a range of phenotypes depending on the type of tumor and their locations in the tumor microenvironment (TME). TAMs are commonly the most abundant infiltrating leukocyte in most tumors and are predominantly thought to have pro-tumor effects. These include both immunosuppressive effects in addition to pro-angiogenic and metastatic effects. The mechanisms by which TAMs have been described to mediate immunosuppression are detailed below.

Amino Acid Depletion and Production of Immunosuppressive Metabolites by Tumor-Associated Macrophages

Tumor-associated macrophages (TAMs) inhibit the anti-tumor immune response through multiple mechanisms. One mechanism is through the depletion of amino acids and the production of immunosuppressive metabolites. Like tumor cells and myeloid-derived suppressor cells (MDSCs), TAMs in several types of human tumors have been shown to overexpress indolamine-2,3-dioxygenase (IDO), which catalyzes the initial, rate-limiting step in L-tryptophan degradation by the kynurenine pathway. The degradation of L-tryptophan and the presence of kynurenine and its derivatives inhibit the proliferation and activity of CD4⁺ and CD8⁺ T cells and natural killer cells and promote the differentiation of regulatory T cells (Tregs). Additionally, murine TAMs also express arginase 1 (ARG1), leading to increased uptake of L-arginine, which reduces the expression of TCR-CD3 zeta chain on T cells and leads to proliferative arrest. Although TAMs appear to mediate immunosuppression through expression of ARG1 in murine tumor models, metabolism of L-arginine by ARG1 in human TAMs has not been conclusively demonstrated to be a mechanism by which T cell functions are suppressed in human tumors.

Expression of Non-Classical HLA Class I Molecules by Tumor-Associated Macrophages

A second mechanism by which TAMs inhibit the anti-tumor immune response is by expression of non-classical human leukocyte antigen (HLA) class I molecules such as HLA-E and HLA-G. Both HLA-E and HLA-G are HLA-class Ib molecules that inhibit the activities of different immune cell types by interacting with specific inhibitory receptors expressed on the surface of immune cells. HLA-E binds to the inhibitory CD94-NKG2A receptor expressed on natural killer (NK) cells or CD8⁺ T cells with six-fold higher affinity than it binds to the CD94-NKG2C activating receptor, and as a result, it can inhibit the proliferation and cytotoxicity of these cells. HLA-G can also inhibit IFN-gamma secretion and the cytotoxicity of NK and CD8⁺ T cells by interacting with either KIR2DL4 or the inhibitory leukocyte immunoglobulin receptor LILRB1/ILT2. Additionally, interaction of HLA-G with LILRB1/ILT2 on CD4⁺ T cells reduces CD4⁺ T cell proliferation and Th1 cytokine production, and induces Th2-type cytokine production, which further inhibits CD8⁺ T cell cytolytic functions and IFN-gamma expression. HLA-G also interacts with LILRB1/ILT2 or LILRB2/ILT4 expressed on dendritic cells and down-regulates the expression of co-stimulatory molecules, CCR7, and IL-12, and inactivates the MHC class II presentation pathway, resulting in suppression of dendritic cell maturation and induction of a tolerogenic DC phenotype. Tolerogenic DCs fail to promote T cell activation, and instead promote regulatory T cell (Treg) development, further promoting tumor immune escape. B cell responses can also be inhibited by interaction of HLA-G with the LILRB1/ILT2 on these cells. HLA-G inhibits B cell proliferation, differentiation, and Ig secretion.

Direct Engagement of T cell Inhibitory and Apoptotic Receptors by Tumor-Associated Macrophages

TAMs may also suppress T cell functions through the direct engagement of T cell inhibitory and apoptotic receptors. TAMs express B7-1/CD80 and B7-2/CD86 which can bind to the T cell-expressed co-inhibitory receptor CTLA-4, with higher affinity than they bind to the CD28 co-stimulatory receptor, resulting in suppression of T cell activation. PD-L1 and PD-L2 are also overexpressed on TAMs in multiple cancer tissues. Both of these ligands bind to PD-1 expressed on CD4⁺ and CD8⁺ effector T cells and can inhibit TCR signaling and promote T cell anergy and apoptosis. B7-H4, another B7 family member expressed by TAMs, binds to an unknown receptor expressed on activated T cells and inhibits IL-2 production, proliferation, and cytokine secretion. TAMs can also directly promote T cell apoptosis through their expression of Fas Ligand (Fas L) and TRAIL, which interact with their respective receptors, Fas/CD95 and TRAIL R2 on CD4⁺ and CD8⁺ effector T cells to mediate apoptosis.

Production of Inhibitory Cytokines by Tumor-Associated Macrophages

Similar to many other immunosuppressive cell types present in the tumor microenvironment, TAMs inhibit the anti-tumor immune response through the production of IL-10 and TGF-beta 1. Together these cytokines inhibit the activation, differentiation, proliferation, and functions of effector T cells. IL-10 and TGF-beta 1 also promote the expansion of suppressive T cells. TGF-beta 1 induces the expression of FoxP3 in CD4⁺CD25- conventional T cells thereby promoting the expansion of regulatory T cells, while IL-10 promotes the conversion of activated conventional T cells to IL-10-, TGF-beta 1-secreting Tr1 cells. In addition, TGF-beta 1 also reduces NK cell proliferation and cytotoxicity, down-regulates NKG2D and NKp30 expression on natural killer (NK) cells and CD8⁺ T cells, promotes the polarization of macrophages toward a M2 phenotype, and inhibits the expression of co-stimulatory molecules and IL-12 by dendritic cells (DCs), as well as DC maturation and migration.

Inhibition of Tumor Cell Phagocytosis by Tumor-Associated Macrophages

TAMs also promote tumor immune evasion through expression of signal regulatory protein alpha (SIRP alpha). SIRP alpha is a receptor for CD47, a cell surface protein that typically protects normal cells from phagocytosis by macrophages or dendritic cells. CD47 is frequently overexpressed on tumor cells and plays a key role in tumor escape by binding to SIRP alpha and sending macrophages a “don’t eat me” signal. Blockade of the CD47-SIRP alpha signal has been shown to stimulate phagocytosis, leading to tumor cell elimination.

Production of Treg-Recruiting Chemokines by Tumor-Associated Macrophages

TAMs may also indirectly inhibit the anti-tumor immune response by producing chemokines such as CCL2, CCL5, CCL20, and CCL22, which are involved in recruiting regulatory T cells (Tregs) to the tumor microenvironment. Tregs subsequently inhibit the activities of CD4⁺ and CD8⁺ effector T cells, natural killer (NK) cells, NKT cells, and antigen-presenting cells (APCs) through multiple mechanisms. These include the production of immunosuppressive cytokines and extracellular adenosine, growth factor depletion, induction of infectious tolerance and apoptosis, and CTLA-4- and LAG-3-mediated inhibition of dendritic cell maturation.

Production of PGE₂ by Tumor-Associated Macrophages

TAMs also inhibit the anti-tumor immune response through production of prostaglandin E2 (PGE₂).TAMs produce high levels of PGE₂ through the up-regulated expression of the PGE₂-producing enzymes, COX2 and PGES1. PGE₂ inhibits IFN-gamma production and the cytolytic activity of natural killer (NK) cells. Additionally, it inhibits the early stages of dendritic cell differentiation, promotes MDSC expansion and suppressive activity, suppresses IL-2 production and responsiveness in T cells, and inhibits NK/Th1/CD8⁺ T cell-mediated immune responses while promoting Th2/Th17/Treg responses.

Monocyte/Macrophage Recruitment to the Tumor Microenvironment

The initial step in TAM-mediated immunosuppression in the TME is the recruitment of these cells to the tumor site. Monocytes are recruited to the tumor microenvironment (TME) by chemokines such as CSF-1, CCL2, and CCL5, which are secreted by tumor cells. Once present in the tumor tissue, monocytes differentiate into macrophages. As a result, macrophages accumulate in tumors, where they play a key role in promoting tumor progression. TAMs secrete growth factors, cytokines, chemokines, and other factors that not only inhibit the anti-tumor immune response, but also drive tumor cell proliferation, angiogenesis, invasion, and metastasis.

To learn more, explore the following macrophage-related resources:

Monocyte/Macrophage Research Area Page

Macrophage and Macrophage Activation State Cell Marker pages

The Complex Biology of Macrophages: Origins, Functions, & Activation States Poster

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