Molecular Repolarisation of Tumour-Associated Macrophages

Abstract

The tumour microenvironment (TME) is composed of extracellular matrix and non-mutated cells supporting tumour growth and development. Tumour-associated macrophages (TAMs) are among the most abundant immune cells in the TME and are responsible for the onset of a smouldering inflammation. TAMs play a pivotal role in oncogenic processes as tumour proliferation, angiogenesis and metastasis, and they provide a barrier against the cytotoxic effector function of T lymphocytes and natural killer (NK) cells. However, TAMs are highly plastic cells that can adopt either pro- or anti-inflammatory roles in response to environmental cues. Consequently, TAMs represent an attractive target to recalibrate immune responses in the TME. Initial TAM-targeted strategies, such as macrophage depletion or disruption of TAM recruitment, have shown beneficial effects in preclinical models and clinical trials. Alternatively, reprogramming TAMs towards a proinflammatory and tumouricidal phenotype has become an attractive strategy in immunotherapy. This work summarises the molecular wheelwork of macrophage biology and presents an overview of molecular strategies to repolarise TAMs in immunotherapy.

Keywords: cancer immunotherapy; repolarisation; small molecules; tumour microenvironment; tumour-associated macrophages.

Figure 1

Schematic representation of the functions of M1 and M2-like macrophages in tumour development. During early stages of tumourigenesis activated (M1) macrophages present antigens and support cytotoxic T lymphocytes (CTL) by the production of proinflammatory cytokines. They eliminate tumour cells with nitrogen and oxygen radicals or by phagocytosis. These antitumour macrophages can be seized by the tumour and shifted to an M2-like state by secretion of immunosuppressive cytokines. The formed M2-like macrophages suppress CTL function and redirect them to immunosuppressive T cell subsets. M2 polarised TAMs support tumour growth in all stages of disease including proliferation, angiogenesis and metastasis.

Figure 2

Schematic representation of the key signalling pathways driving macrophage polarisation. M1 stimuli as IFNγ, bacterial lipoproteins or lipopolysaccharides induce IRF3, IRF5, IRF7, STAT1 and P50-P65 NFκβ signalling leading to a proinflammatory response. In contrast, M2 stimuli as IL4, IL10 and IL13 activate IRF4, STAT3, STAT6 and P50-P50 NFκβ signalling resulting in anti-inflammatory gene expression and tumour progression. The crosstalk between these regulatory pathways determines the exact outcome of macrophage activity.

Figure 3

Structure of small molecule TLR agonists with potential TAM reprogramming abilities.

Figure 4

Chemical structure of TAM reprogramming small molecules.