Diverse Functions of Macrophages in Different Tumor Microenvironments

Abstract

Tumor-associated macrophages are a major constituent of malignant tumors and are known to stimulate key steps in tumor progression. In our review in this journal in 2006, we postulated that functionally distinct subsets of these cells exist in different areas within solid tumors. Here, we review the many experimental and clinical studies conducted since then to investigate the function(s), regulation, and clinical significance of macrophages in these sites. The latter include three sites of cancer cell invasion, tumor nests, the tumor stroma, and areas close to, or distant from, the tumor vasculature. A more complete understanding of macrophage diversity in tumors could lead to the development of more selective therapies to restore the formidable, anticancer functions of these cells. Cancer Res; 78(19); 5492-503. ©2018 AACR.

Figure 1. Macrophages in pre-invasive lesions.

Epithelial cells within the basement membrane (BM) undergo transformation in response to a number of stimuli. This causes them to release factors that stimulate both the recruitment of Ly6C+ monocytes and the migration and/or gene expression of surrounding macrophages. These include CSF1, CCL2, EGF, MMPs and cathepsins. Co-operation may takes place between invading cancer cells (expressing CSF1) and macrophages (expressing EGF), to facilitate the movement of cancer cells towards neighboring blood vessels. Perivascular VEGFA+ macrophages then promote the escape of cancer cells into the circulation. Macrophage release of VEGFA also stimulates angiogenesis as pre-invasive lesions progress to invasive ones. Invading cancer cells are protected from anti-tumor immunity by the expression of PD-L1 and IL-23 by macrophages in such sites. (green - macrophages; blue - epithelial/cancer cells; red - blood vessels).

Figure 2. The phenotype of TAMs in different compartments within established primary tumors.

A small sub-compartment within a tumor is shown consisting of 3 tumor ‘nests’ (areas of high cancer cell density) containing hypoxic/necrotic (H/N) areas; the tumor-stroma border (TSB) at the edge of tumor nests (grey dashed line); the stroma (which in most solid tumors is highly vascularized; red); and an invasive front (IF) between this part of the tumor mass and surrounding non-malignant tissue (pink). [Box – cell surface markers, enzymes and cytokines expressed by TAMs in these different regions. The main functions of the various TAM subsets have also been listed].