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.

Inflammatory Responses during Tumour Initiation: From Zebrafish Transgenic Models of Cancer to Evidence from Mouse and Man

“…For example, the immunosuppressive effect of PGE 2 could prevent neutrophils from performing anti-tumour activities and may contribute to the M2/N2 phenotype of pro-tumour leukocytes. Indeed, COX-2 inhibitors have been shown to repolarize M2 TAMs [220][221][222], and PGE 2 has been implicated in the induction of MDSCs in tumour-bearing mice [223][224][225].…”

“…Moreover, a more potent effect may be achieved by developing strategies to reprogram macrophages and neutrophils to an 'M1' or 'N1' state, wherein they may partake in anti-tumour responses. Some promise has been shown in this area, regarding the reprogramming of TAMs in mouse models [175,220,235,236], but this is yet to be explored in zebrafish. Traditional methods for studying leukocyte polarisation in mammalian immunology involve the analysis of multiple cell surface markers by flow cytometry, a method which is not compatible with zebrafish due to a lack of zebrafish-specific antibodies.…”

Evaluating the Polarization of Tumor-Associated Macrophages Into M1 and M2 Phenotypes in Human Cancer Tissue: Technicalities and Challenges in Routine Clinical Practice

“…Activated macrophages are often classified as proinflammatory M1 macrophages or anti-inflammatory M2 macrophages. The M1-like phenotype is induced by toll-like receptor ligands (bacterial lipopolysaccharide) or Th1 cytokines, such as tumor necrosis factor alpha (TNF-α), interferon gamma (IFNγ ) and colony stimulating factor 2 (CSF2) (3,4). M1-like macrophages exert high antigen presenting capacity (5).…”

“…M2-like macrophages, on the other hand, are polarized by Th2-derived cytokines such as IL4, IL10, IL13, transforming growth factor beta (TGFβ) or prostaglandin E2 (PGE2) (3). They are known as the "repair" or "fix" macrophages as they promote tissue repair via immune tolerance and tissue remodeling, debris scavenging and immune modulation (7).…”

“…They are known as the "repair" or "fix" macrophages as they promote tissue repair via immune tolerance and tissue remodeling, debris scavenging and immune modulation (7). When it comes to cancer, M2-like macrophages support angiogenesis by secreting adrenomedullin and vascular epithelial growth factors (VEGFs) and express immunosuppressive molecules such as IL10, programmed death-ligand 1 (PD-L1), and TGFβ, favoring tumor growth (3). They are regarded as "friends" by cancer cells.…”