The complex role of tumor-infiltrating macrophages

Abstract

Long recognized as an evolutionarily ancient cell type involved in tissue homeostasis and immune defense against pathogens, macrophages are being re-discovered as regulators of several diseases, including cancer. Tumor-associated macrophages (TAMs) represent the most abundant innate immune population in the tumor microenvironment (TME). Macrophages are professional phagocytic cells of the hematopoietic system specializing in the detection, phagocytosis and destruction of bacteria and other harmful micro-organisms, apoptotic cells and metabolic byproducts. In contrast to these healthy macrophage functions, TAMs support cancer cell growth and metastasis and mediate immunosuppressive effects on the adaptive immune cells of the TME. Cancer is one of the most potent insults on macrophage physiology, inducing changes that are intimately linked with disease progression. In this Review, we outline hallmarks of TAMs and discuss the emerging mechanisms that contribute to their pathophysiological adaptations and the vulnerabilities that provide attractive targets for therapeutic exploitation in cancer.

Fig. 1 |. In tumor-bearing hosts, tumor-released factors drive increased production and output of classical Ly6C⁺ monocytes and mDSCs from myeloid progenitors of the Bm.

a–c, After egress, BM-derived monocytes, M-MDSCs, and PMN-MDSCs are recruited to the primary tumor (a) and metastasis sites (b,c) through chemotactic factors produced by cancer cells, tumor-associated fibroblasts, and TAMs. After localizing at the tumor, BM-derived monocytes and M-MDSCs differentiate to TAMs and promote cancer growth. In contrast to classical monocytes that give rise to TAMs, nonclassical patrolling monocytes seem to have a protective role against cancer progression because they accumulate at the sites of lung metastasis, produce IL-15, and orchestrate the recruitment and activation of NK cells, thereby inhibiting cancer invasion and growth. During cancer evolution, tissue-resident macrophages (TRMs) derived from embryonic hematopoietic organs, such as alveolar macrophages in the lung (b) and KCs in the liver (c) are the first to be subject to the effects of cancer-produced soluble factors, as well as other TME insults (a). They undergo early inflammatory changes, assist in the recruitment of BM-derived monocytes, and contribute to the generation of TAMs. In metastatic sites, TRMs might foster formation of the premetastatic niche (b,c). C5a receptor, complement receptor 5a. growth factors: M-CSF, gM-CSF; cytokines: IL-6, IL-1, IL-8; chemokines: CCL2, CCL5, CXCL12, CCL4; DAMPs: DNA, RNA, exosomes, uric acid, ATP, metabolites. HSC, hematopoietic stem cell; MDP, monocyte-DC progenitor.

Fig. 2 |. recruitment of Bm-derived monocytes in tumors and subsequent conversion to TAms requires activation of α₄β₁ integrin.

IL-1β, SDF1α, and VEgF activate receptor tyrosine kinases (RTK), g-protein-coupled receptors (gPCR), and TLR/IL-1R, leading to activation of Ras and its downstream target phosphoinositide 3-kinase γ (PI3Kγ), initiating a signaling cascade that leads to integrin activation. Activation of PI3Kγ inhibits signaling through the transcription factor NF-κB while promoting c/EBPβ-mediated signaling leading to the generation of immunosuppressive TAMs. Various subsets of TAMs within the same tumor have unique functional roles in supporting cancer growth. TAMs expressing the angiopoietin receptor Tie2 accumulate at the perivascular areas, where they support angiogenesis and tumor growth. TAMs are recruited to avascular, hypoxic tumor areas through the semaphorin 3A (Sema3A)–neuropilin-1 (Nrp1) pathway, where Nrp1 is downregulated and Sema3A entraps TAMs locally through plexinA1–plexinA4-mediated stop signals. Upregulation of REDD1, a negative regulator of mTOR, prevents glycolysis and promotes angiogenesis. Certain TAM subsets produce MMPs, which promote tissue remodeling, thereby facilitating monocyte and cancer cell migration, intravasation, and metastasis.

Fig. 3 |. Cancer-related inflammation is initiated by hematopoietic growth factors, cytokines, and chemokines produced by cancer cells as a consequence of oncogene-mediated malignant transformation.

There is proinflammatory activation from DAMPs produced by cancer cells due to rapid replication and apoptosis, nutrient starvation, and hypoxia. Exosomes released from cancer cells, containing tumor DNA or RNA, contribute to the proinflammatory TME. Cytokines activate immune and cancer cells, whereas DAMPs are recognized by pattern recognition receptors (PRRs) expressed by macrophages and other cells of the innate immune system, such as dendritic cells (DCs), as well as cancer cells, to initiate proinflammatory cascades. In response to inflammatory activation, TAMs express Tim3, Tim4, PD-1, and PD-L1 checkpoint inhibitors, which can inhibit macrophage functions and synergize with the Sirp1a–CD47 pathway to inhibit phagocytosis of cancer cells. Cancer-produced cytokines and DAMPs also act on BM progenitors through cytokine and growth factor receptors and PRRs to induce myelopoiesis, which gives rise to immature immunosuppressive PMN-MDSCs and M-MDSCs, the latter being recruited into the tumor to become TAMs. CTL, cytotoxic T lymphocyte.

Fig. 4 |. Changes of TAms during cancer immunoediting.

During the elimination phase, macrophages eliminate cancer cells by phagocytosis and activation of anti-tumor T cell responses by presentation of tumor-associated antigens, whereas these immune functions are compromised during cancer progression to immune equilibrium and escape. While TRMs predominate during elimination, BM-derived TAMs increasingly enter the tumor during the immune equilibrium phase, leading to increasing local inflammation. During the immune escape phase, in response to tissue residence and cues of the TME, TRMs and BM-derived TAMs acquire similar properties, characterized by enhanced proinflammatory and diminished pro-resolving signaling.