Tumour-associated macrophages and cancer

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Highlights

  • TAM infiltration is linked to a poorer prognosis and resistance to therapy in several cancer types.

  • Challenges are faced due to lack of TAM specific markers.

  • Next generation sequencing methods have improved TAM characterisation.

  • Inhibition of TAM recruitment represents an attractive target for anti-tumour therapy.

  • Combining TAM inhibition with standard therapy has shown promise in early results.

Our understanding of the complex roles and functions of tumour-associated myeloid cells has improved vastly over the last few years. Alternatively activated macrophages, TAMs, are an abundant part of solid and haematological malignancies and have been linked with progression, metastasis and resistance to therapy. Still, characterisation and TAM targeting is hindered by a lack of TAM specific markers, but advances in next generation technologies are rapidly increasing our understanding of the sheer diversity of myeloid differentiation and phenotypic regulation. These technologies help to shed light on the heterogeneous phenotypic states of myeloid cells within the tumour. Alternative approaches to influence the myeloid compartment within cancers surround inhibition of myeloid recruitment or ‘re-education’ of the plastic TAM phenotype. Our knowledge continuously grows on how even ‘established’ therapies might influence the myeloid compartment within tumours. Now the promising results from elegant pre-clinical studies at first translate into the clinic and use combination therapies with myeloid inhibitors and standard chemotherapy.

Section snippets

Macrophages, cancer and inflammation

Infiltrating immune cells are an abundant component of solid tumours [1, 2, 3]. The complex balance between pro-tumoural and anti-tumoural effects of immune cell infiltration is thought to create a chronic inflammatory microenvironment essential for tumour growth, progression and invasion [4, 5, 6•, 7, 8].

Macrophages are often found in the stromal compartment of solid tumours including breast, ovarian, pancreatic and hepatocellular carcinomas [9, 10, 11, 12]. Macrophages are part of the

Macrophage phenotypic characterisation

Phenotypic plasticity of macrophages allows them to adapt in response to environmental signals, which is key in innate immunity. Currently the macrophage phenotype is often simplified as either classical ‘M1’ or alternative ‘M2’ [14]. Although, it is now acknowledged that there is a spectrum of intermediate phenotypes that may also have different functional abilities [15, 16].

Classically activated macrophages or ‘M1’ like macrophages activate cells of the adaptive immune system and are

Tumour associated macrophage characterisation

A recent meta-analysis, taking into account recent exploitable data from 55 studies, summarised the current prognostic value of macrophage presence in cancer. Macrophage presence was associated with decreased survival in endometrial, prostate, urothelial bladder, ovary, gastric and oral carcinomas. The most striking effects were seen in breast cancer where the detrimental effects of TAM presence were found on clinical staging, vascular invasion, tumour volume, lymph node metastasis and HER-2

Inhibition of macrophage recruitment for anti-cancer therapy

Alternatively activated TAMs are an attractive target due to their range of tumour promoting roles and plasticity to reduce the surrounding inflammatory microenvironment and enhance anti-tumour activity [40, 8, 41•]. Current pre-clinical investigations into TAM abrogration as an anti-cancer strategy have shown promising results in murine models of breast and pancreatic cancer [29•, 42]. Clodronate was used for quite some time in many tumour studies to dissect the impact of macrophages on tumour

‘Re’-educating the TAM phenotype

Macrophages are highly abundant in the tumour microenvironment  this makes them a highly interesting clinical therapeutic target, as their genetic programmes are most likely more stable than those of malignant cells. In addition, to be able to adapt the macrophage phenotype in a temperospatial manner according to the therapeutic desirable response is highly attractive.

Pre-clinical studies have demonstrated that this approach is feasible. Data from our own group showed that by targeting the NF-κB

Challenges

Current understanding implicates macrophages in complex, diverse tumour-promoting roles within the tumour microenvironment. To mount an effective therapeutic offensive requires a well-founded understanding of macrophage phenotypic variation and interaction with tumour cells as well as identification of specific TAM markers. So far, re-programming of the tumour microenvironment to enhance anti-tumoural effects by targeting macrophages in early pre-clinical studies shows potential and the results

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

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