Immunometabolic Interplay in the Tumor Microenvironment

Abstract

Immune cells' metabolism influences their differentiation and function. Given that a complex interplay of environmental factors within the tumor microenvironment (TME) can have a profound impact on the metabolic activities of immune, stromal, and tumor cell types, there is emerging interest to advance understanding of these diverse metabolic phenotypes in the TME. Here, we discuss cell-extrinsic contributions to the metabolic activities of immune cells. Then, considering recent technical advances in experimental systems and metabolic profiling technologies, we propose future directions to better understand how immune cells meet their metabolic demands in the TME, which can be leveraged for therapeutic benefit.

Keywords: immunology; immunometabolism; in vitro modeling; metabolism; metabolomics; physiologic media; stable isotope tracing; tumor microenvironment.

Figure 1:. Factors influencing metabolism in the TME.

Metabolic conditions in the TME are influenced by many factors. From the perspective of the tumor, mutations in oncogenes and tumor suppressor genes can promote cell-intrinsic changes in metabolic reprogramming depending on the cancer type (“Origin”). Whole body metabolism dictates available nutrients in circulation (“Nutrient Availability”), while local nutrient availability in the TME is influenced by tumor vascularization and tissue nutrient uptake. Due in part to the high proliferation of cancer cells, nutrient and oxygen gradients can form which shape the metabolic activities of cells differently across the tumor. Nutrient utilization and signaling by many cell types present (immune, stromal, epithelial, cancer) in the TME can also modulate the metabolic conditions within the growing tumor (“Tumor-Immune Crosstalk”).

FIGURE 2:. Approaches for modeling physiologic immunometabolism using stable isotope tracing.

Isotope tracers, in the form of heavy-labeled metabolites, can be administered intravenously (top) or ex vivo to sorted cell populations (bottom) to achieve accurate tracing of in vivo metabolic pathways. Ex vivo tracing (bottom), in combination with physiologic media and oxygen tension, offers a path for physiological modeling of the metabolic state of specific cell subsets in vivo that require extensive sorting after extraction.