The Interface of Tumour-Associated Macrophages with Dying Cancer Cells in Immuno-Oncology

Abstract

Tumour-associated macrophages (TAMs) are essential players in the tumour microenvironment (TME) and modulate various pro-tumorigenic functions such as immunosuppression, angiogenesis, cancer cell proliferation, invasion and metastasis, along with resistance to anti-cancer therapies. TAMs also mediate important anti-tumour functions and can clear dying cancer cells via efferocytosis. Thus, not surprisingly, TAMs exhibit heterogeneous activities and functional plasticity depending on the type and context of cancer cell death that they are faced with. This ultimately governs both the pro-tumorigenic and anti-tumorigenic activity of TAMs, making the interface between TAMs and dying cancer cells very important for modulating cancer growth and the efficacy of chemo-radiotherapy or immunotherapy. In this review, we discuss the interface of TAMs with cancer cell death from the perspectives of cell death pathways, TME-driven variations, TAM heterogeneity and cell-death-inducing anti-cancer therapies. We believe that a better understanding of how dying cancer cells influence TAMs can lead to improved combinatorial anti-cancer therapies, especially in combination with TAM-targeting immunotherapies.

Keywords: TAM heterogeneity; apoptosis macrophage targeting; cancer therapy; chemotherapy; immunogenic cell death; immunotherapy; macrophages; radiotherapy; tumour microenvironment.

Figure 1

Schematic overview of macrophage development into different classes. Macrophages differentiated from bone marrow and embryonic precursors, different phenotypes will arise according to the tissue origin or organs (a). The two main classes of macrophages are classically activated macrophages (M1) and alternatively activated macrophages (M2). Macrophages differentiated into M1-like macrophages express high levels of main histocompatibility complex II (MHC-II) and clusters of differentiation (CD). Once activated, M1-like macrophages can generate nitric oxide (NO) and secrete interleukins (ILs) and tumour necrosis factor α (TNF α). M1-like macrophages will induce an anti-tumour effect and will interact with dying cancer cells by efferocytosis to recruit more immune cells (b). On the contrary, M2-like macrophages express multiple CDs, CSF1-receptor (CSF1R) and macrophage galactose-type lecin-1 (MGL1). Once M2-like macrophages are activated, they can secrete IL8 and IL10, matrixmetalloproteinase-2, -7 and -9 (MMP2, MMP7 and MMP9) and arginase, hereby stimulating tumour progression (c). Migration and infiltration of macrophages in a tumour environment give rise to various tumour-associated macrophages (TAMs) subsets. TAMs resemble mostly M2-like macrophages by secreting IL-10, TGFβ and C-C motif chemokine ligands 3 and 4 (CCL3 and CCL4). When TAMs act as M1-like macrophages, they will release pro-IL1, IL6 and IFNγ (d). Other subtypes of macrophages can occur depending on the stimuli present in specific tissue or organs (e).

Figure 2

Overview of the impact of cell death due to tumour-associated stress or induced by anti-cancer therapy and the effect of immunotherapy on TAMs. In hypoxic and necrotic areas, recruitment of TAMs occurs through expression of chemoattractant molecules, such as C-C motif chemokine ligands 2 and 5 (CCL2 and CCL5), C-X-C motif chemokine ligand 12 (CXCL12), endothelin, vascular endothelial growth factor (VEGF), endothelial monocyte-activating polypeptide-II (EMAP-II), oncostatin M and eotaxin. Once in hypoxic areas, the conditions will downregulate C-C motif chemokine receptors 2 and 5 (CCR2 and CCR5) causing retention and entrapment of TAMs in the tumour. This will induce transcription in TAMs by upregulating hypoxia-inducible factors-1 and -2 (HIF-1, HIF-2). Simultaneously, hypoxia can promote surface expression of VEGF receptor, platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR). Besides hypoxia, acidosis and nutrient starvation can both affect macrophage metabolism leading to pro-tumour effects (a). Cancer cells undergoing apoptosis will expose eat-me signals, such as phosphatidylserine (PS) and sphingosine-1-phosphate (S1P), which can reduce production of interleukin 12 (IL 12) and downregulate main histocompatibility complex-II (MHC-II) presented by TAMs. Both accidental and programmed necrosis (i.e.,) necroptosis, secrete eat-me signals that will cause a pro-tumour effect (b). Chemotherapy can induce cell death, resulting in high expression of colony-stimulating factor 1 (CSF1) on the cancer cells. This will attract CSF1-receptor (CSF1R) positive macrophages together with TAMs, which secrete stimulatory factors to recruit other immune-suppressive myeloid cells. However, certain chemotherapies can induce immunogenic apoptosis leading to exposure/secretion of calreticulin (CRT), intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 and adenosine triphosphate (ATP). When deficiency in the apoptosis pathway, necrosis is stimulated, and the interaction of released high mobility group box 1 (HMGB1) with Toll-like receptors (TLRs) triggers pro-inflammation (c). Depending on the doses, radiotherapy can reprogram TAMs to a phenotype sustained by nuclear factor kappa-light-chain-enhancer of activated B cells B (NFκB) p50 activation that leads to IL10 and tumour necrosis factor α (TNFα) secretion. Low doses can induce secretion of damage-associated molecular patterns (DAMPs) and upregulation of cluster of differentiation 86 (CD86) (d). Limiting of TAMs at tumour sites can be performed by blocking C-C chemokine receptors 2 and 5 (CCR2 and CCR5). Repolarisation of the TAMs is performed by blocking the CSF1-CSF1R interaction through antibodies, by inhibiting tyrosine kinases or by blocking CD47. Depleting TAMs can be performed by using clodronate liposomes to induce apoptosis. Lastly, CAR macrophages can induce phagocytosis of cancer antigens (e).