Immunology in the clinic review series; focus on cancer: tumour-associated macrophages: undisputed stars of the inflammatory tumour microenvironment

Abstract

Mononuclear phagocytes are cells of the innate immunity that defend the host against harmful pathogens and heal tissues after injury. Contrary to expectations, in malignancies, tumour-associated macrophages (TAM) promote disease progression by supporting cancer cell survival, proliferation and invasion. TAM and related myeloid cells [Tie2(+) monocytes and myeloid-derived suppressor cells (MDSC)] also promote tumour angiogenesis and suppress adaptive immune responses. These divergent biological activities are mediated by macrophages/myeloid cells with distinct functional polarization, which are ultimately dictated by microenvironmental cues. Clinical and experimental evidence has shown that cancer tissues with high infiltration of TAM are associated with poor patient prognosis and resistance to therapies. Targeting of macrophages in tumours is considered a promising therapeutic strategy: depletion of TAM or their 're-education' as anti-tumour effectors is under clinical investigation and will hopefully contribute to the success of conventional anti-cancer treatments.

Fig. 1

Macrophage polarization is modulated by microenvironmental signals. T helper type 1 (Th1) cytokines [e.g. interferon (IFN-γ)] and Toll-like receptor (TLR) ligands [e.g. lipopolysaccharide (LPS)] promote M1 macrophages which elicit Th1 immune responses and fight intracellular pathogens. Th1 cells produce IFN-γ, which further sustains M1 polarization. Th2 cytokines [e.g. interleukin (IL)-4, IL-13], IL-10 and glucocorticoids promote M2 macrophages which block Th1 immune responses and promote wound healing, scavenging of damaged tissues and angiogenesis. Th2 cells produce IL-4, which further sustains M2 polarization.

Fig. 2

Pro-tumour functions of tumour-associated macrophages (TAM). TAM promote the survival of neoplastic cells from apoptotic stimuli and their proliferation, by producing several growth factors and cytokines [e.g. epithelial growth factor (EGF), interleukin (IL)-6], and the tumour angiogenesis, via vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMPs) and other angiogenic factors. TAM have an intense proteolityic activity and degrade the extracellular matrix, but also produce matrix proteins, such as fibronectin (FN1). They favour tumour cell intravasation and dissemination to distant sites. TAM have immune suppressive functions by producing IL-10 and transforming growth factor (TGF-β) which suppress T helper type 1 (Th1) lymphocytes, and by secreting chemokines (e.g. CCL17, CCL18, CCL22) which recruit lymphoid cells devoid of cytotoxic activity (Th2, naive lymphocytes) or having suppressive functions [regulatory T cells (T_reg)].