Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: Potential targets of anti-cancer therapy
Introduction
Accumulation of leukocyte subpopulations is the hallmark of several pathological conditions, including tumours.1 A prominent component of solid tumours is represented by non-tumoural cells, including stromal cells (fibroblasts and endothelial cells) and leukocytes. Among the latter, macrophages are the major component.2 Tumour-associated macrophages (TAM) have been studied extensively for their relationship with tumour cells and their multi-faceted functions in the tumour micro-environment. Immunologists have long considered the presence of TAM as evidence of a host response against the growing tumour. Several studies have demonstrated that macrophages have the potential to kill tumour cells in vitro when appropriately stimulated, e.g. following treatment with lipopolysaccharides (LPS) and interferon (IFN)-γ. However, bacterial stimuli and Th1 cytokines inducing M1 type polarisation are usually not present at the tumour site. Here, in contrast, differentiating macrophages are likely to encounter factors that most frequently polarise them toward M2 type macrophages (e.g. interleukin (IL)-10). Over the years it has become increasingly clear that TAM are active players in the process of tumour progression and invasion. In several experimental tumour models, the activation of an inflammatory response (most frequently mediated by macrophages) is essential for full neoplastic transformation and progression.3 Furthermore, in clinical studies high numbers of intra-tumour macrophages correlate with high vessel density and tumour progression.
The strategic location of TAM suggests that these cells are important regulators of anti-tumour immunity. Characterisation of the phenotype of TAM is therefore essential to the understanding of tumour-derived signals guiding polarisation of innate and adaptive immunity in cancer bearers and to the identification of molecular mechanisms that might be amenable to therapeutic intervention.
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Monocyte-macrophages
Since the first observation by Rudolf Virchow, who noticed the infiltration of leukocytes into malignant tissues and suggested that cancers arise at regions of chronic inflammation, the origin of TAM has been studied in terms of recruitment, survival and proliferation. TAM derive from circulating monocytes and are recruited at the tumour site by a tumour-derived chemotactic factor for monocytes, originally described by this group4 and later identified as the chemokine CCL2/MCP-15, 6 (Fig. 1).
Distinct properties of M1 and M2 macrophages
The ability to express distinct functional programs in response to different micro-environmental signals is a biological feature of macrophages, which is typically manifested in pathological conditions such as infections and cancer.39, 40 Chronic infections can tightly regulate the immune responses, being able to trigger highly polarised type I or type II inflammation and immunity. Central to the development of type I or type II polarisation is the specificity of the host–pathogen interaction.
TAM express selected M2 pro-tumoural functions
The cytokine network expressed at the tumour site plays a central role in the orientation and differentiation of recruited mononuclear phagocytes, thus contributing to direct the local immune system away from anti-tumour functions.2 This idea is supported by both pre-clinical and clinical observations18, 44 that clearly demonstrate an association between macrophage number/density and prognosis in a variety of murine and human malignancies.
The immunosuppressive cytokines IL-10 and transforming
Modulation of adaptive immunity by TAM
It has long been known that TAM have poor antigen-presenting capacity and can actually suppress T cell activation and proliferation.2 The suppressive mediators produced by TAM include prostaglandins, IL-10 and TGF-b and indoleamine dioxigenase (IDO) metabolites.2, 44 Moreover, TAM are unable to produce IL-12, even upon stimulation by IFN-γ and LPS.49 With this cytokine profile, which is characteristic of M2 macrophages, TAM are unable to trigger Th1 polarised immune responses, but rather induce
TAM as a therapeutic target
Two major functions of TAM potentially amenable to therapeutic interventions are their recruitment and cytotoxicity. TAM accumulate preferentially in the poorly vascularised region of tumours, which are characterised by low oxygen tension. Such an environment promotes TAM adaptation to hypoxia, which is achieved by the increased expression of hypoxia inducible and pro-angiogenic genes, such as VEGF, bFGF and CXCL8, whose transcription is controlled by the transcription factors HIF-1 and HIF-2.64
Conclusion
Though the presence of TAM has long been considered as evidence for a host response against the growing tumour, it has become increasingly clear that TAM are active players in the process of tumour progression and invasion. Molecular and biological studies have been supported by a large number of clinical studies that have found a significant correlation between the high macrophage content of tumours and poor patient prognosis. TAM share many similarities with prototypic polarised M2
Conflict of interest statement
None declared.
Acknowledgements
This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC), Italy; by Ministero Istruzione Università Ricerca (MIUR), Italy; Istituto Superiore Sanita’ (ISS); by Progetto NOBEL by Fondazione Cariplo; European Commission (FP6, DC-THERA project no 512074).
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