Abstract
ABSTRACTThe extracellular space of solid tumors ranges from being well-nurtured to being completely ischemic and can serve as a source of intratumoral heterogeneity, determining the behavior and molecular profiles of malignant and stromal cells. Here, we discuss how the metabolic tumor microenvironment modulates the phenotypes of the immune cells that infiltrate tumors, with an emphasis on tumor-associated macrophages. These cells constitute a diverse population that has pro-tumoral and anti-inflammatory properties, and are likened to anti-inflammatory ‘M2’ macrophages. Recent findings show how different metabolic microenvironments specify an array of phenotypic changes in macrophages. In tumors, extracellular metabolite levels vary predictably according to proximity to the vasculature, and phenotypic changes in tumor-associated macrophages and in other immune cells are also predictable. We speculate that this ‘metabolic axis’ of macrophage polarization modulates – and is modulated by – the response to inflammatory cues, creating a wide variety of possible phenotypic states. Understanding how extracellular metabolites influence cell phenotypes allows us to predict how tumor-associated macrophages and other tumor cells might change, with the aim of harnessing this predictability for therapy. Overall, we describe an emerging picture in which chemokines, growth factors and the metabolic tumor microenvironment act together to determine the phenotypes of tumor-infiltrating immune cells.
Highlights
Interactions between cancer and immune cells play a crucial role in tumor initiation, growth and metastasis
Tumor-associated macrophages (TAMs; see Glossary, Box 1) are abundant within tumors and have been shown to enhance tumor malignancy; the ability to inhibit these pro-tumoral effects could open up potentially new therapeutic avenues (De Palma and Lewis, 2013; Murray, 2017; Noy and Pollard, 2014; Quail and Joyce, 2017)
The regulation of cell metabolism is recognized to be a crucial aspect of the immune system (Ganeshan and Chawla, 2014; O’Neill and Hardie, 2013; Olenchock et al, 2017; Pearce et al, 2009)
Summary
Interactions between cancer and immune cells play a crucial role in tumor initiation, growth and metastasis. Under conditions of nonlethal ischemia, acidosis, hypoxia and nutrient deprivation, metabolites can act as signals that modulate cellular functions (Fig. 1) (Buck et al, 2017; Carmona-Fontaine et al, 2017; Gatenby and Gillies, 2004) This tumor-induced metabolic diversity suggests that infiltrating macrophages could experience a variety of different microenvironments, but first we need to understand how macrophages alter their phenotype under normal homeostasis.
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