Metabolic guidance and stress in tumors modulate antigen-presenting cells

Abstract

Successful antitumor immunity largely relies on efficient T cell priming by antigen-presenting cells (APCs); however, the capacity of APCs is found to be defective in many cancers. Metabolically reprogrammed cancer cells support the energetic and biosynthetic demands of their high proliferation rates by exploiting nutrients available in the tumor microenvironment (TME), which in turn limits proper metabolic reprogramming of APCs during recruitment, differentiation, activation and antigen presentation. Furthermore, some metabolites generated by the TME are unfavorable to antitumor immunity. This review summarizes recent studies on the metabolic features of APCs and their functionality in the TME. Particularly, we will describe how APCs respond to altered TME and how metabolic byproducts from cancer and immunomodulatory cells affect APCs. Finally, we introduce the current status of APC-oriented research and clinical trials targeting metabolic features to boost efficient immunotherapy.

Fig. 1. Metabolic alteration of TME affecting the immunogenic function of DCs.

Low pH resulting from lactate from tumor cells leads to the downregulation of cAMP, IL-6, and IL-12 by stimulating GPR81. Furthermore, lactate limits the APC function of DCs by suppressing MHCII-mediated antigen presentation and inducing a conformational change of mannose receptor (MR), which is responsible for antigen (Ag) binding. A hypoxic environment limits the migration of DCs to the LN, and enrichment of IDO and adenosine induce DCs to express immunosuppressive cytokines. Fatty acid oxidation (FAO) fueled by lipids in TME is prominently used by dysfunctional DCs that are impaired with antigen cross-presentation. Lipid uptake by scavenger receptor A (SR-A) results in the accumulation of lipids within DC, which consequently affects peptide-MHCI (pMHCI) trafficking by forming an adduct with heat shock protein 70 (HSP70).

Fig. 2. Metabolic interplay between tumor cells and TAMs within TME.

Lactate transported by MCT1 and GPCRs (e.g., OLFR78 and GPR132) shapes pro-tumoral properties of TAMs by upregulating M2-associated genes. Enrichment of TCA cycle metabolites affects the metabolic properties of TAMs. SUCNR1-mediated succinate uptake activates PI3K-HIF1α signaling to induce polarization of TAMs. Furthermore, accumulation of kynurenine within TAMs generated from tryptophan and 2-HG (generated by mutant IDH on tumor cells) by sequential activities of IDO and TDO, binds to aryl hydrocarbon receptor (AhR), and suppresses NF-κB signaling. Glutaminolysis produce α-ketoglutarate (αKG), supplying intermediate for the TCA cycle, and further alters the epigenome of macrophages. Increased dependency on fatty acid oxidation (FAO) or ER stress induced by lipids enriched in TME leads macrophages to adopt pro-tumoral characteristics.