Targeting Metabolism to Improve the Tumor Microenvironment for Cancer Immunotherapy

Abstract

The growing field of immune metabolism has revealed promising indications for metabolic targets to modulate anti-cancer immunity. Combination therapies involving metabolic inhibitors with immune checkpoint blockade (ICB), chemotherapy, radiation, and/or diet now offer new approaches for cancer therapy. However, it remains uncertain how to best utilize these strategies in the context of the complex tumor microenvironment (TME). Oncogene-driven changes in tumor cell metabolism can impact the TME to limit immune responses and present barriers to cancer therapy. These changes also reveal opportunities to reshape the TME by targeting metabolic pathways to favor immunity. Here we explore current strategies that shift immune cell metabolism to pro-inflammatory states in the TME and highlight a need to better replicate physiologic conditions to select targets, clarify mechanisms, and optimize metabolic inhibitors. Unifying our understanding of these pathways and interactions within the heterogenous TME will be instrumental to advance this promising field and enhance immunotherapy.

Figure 1.. Tumor microenvironment and associated immune cell metabolism.

The tumor microenvironment (TME) is often characteristic of nutrient competition, low pH, limited oxygen, and accumulation of metabolites. Such conditions, in general, results in immunosuppressive or tolerogenic phenotypes of immune cells and encourages metabolism that rely more on oxidative phosphorylation and fatty acid oxidation to fulfill energy needs. Additionally, the TME accelerates T effector cell exhaustion followed by increased immune checkpoint expression on these cells. These conditions also promote differentiation and accumulation of Treg, M2-like macrophages, and MDSCs. The TME also produces unique subsets of myeloid cells known as tumor-associated dendritic cells (TADC) and tumor associated neutrophils (TAN) that have yet to fully characterized but are suggested to have suppressive or tolerant phenotypes. (MDSCs, myeloid-derived dendritic cells; Teff, effector T cell)

Figure 2.. Potential therapeutic targets within glucose metabolism pathways.

A) Immune checkpoint blockades have emerged as a promising immune targeted strategy that has been approved clinically for a variety cancer types. Increased expression of checkpoint receptors is often the result of low glucose, acidity or lactate within the tumor microenvironment and engagement of these receptors causes an immunosuppressive phenotype characteristic of decreased glycolysis and increased FAO. Antibodies targeted against these checkpoint receptors have been successful at restoring glycolysis which in turn supports anti-tumor effector functions within immune cells. However due to the variability of immune checkpoint expression on immune cells, the most promising utilization will involve combination therapies coupling ICB with one or multiple other metabolic targets. B) Accumulation of lactate in the tumor microenvironment has been found to promote immunosuppressive immune cells through M2 macrophage polarization, MDSC infiltration, Treg survival and by inhibiting T effector functions. Strategies that decrease lactate accumulation through inhibiting lactate producing enzyme LDH, inhibiting lactate transporters, MCT1/4, or neutralizing lactic acid induced acidity have proved effective at improving antitumor immune cells. Recently utilization of acidic pH selective Abs against checkpoint receptor VISTA provides an intriguing strategy that exploits the TME to improve treatment specificity. However, targeting these pathways can be TME context and immune cell specific therefore a clear mechanism for these anticancer effects is still unclear. (ICB, Immune Checkpoint Blockades; LDH, lactate dehydrogenase; MCT, monocarboxylate transporter)

Figure 3.. Promising strategies that alter amino acid metabolism within the TME.

A) Glutamine metabolism is altered as a result of the tumor microenvironment. Inhibiting glutaminolysis through blocking glutaminase (GLS) has proved to promote a proinflammatory macrophage phenotype. However specific T cell subsets can be GLS dependent or independent and thus GLS targets can have differential effects in T cell populations. B) Therapies that facilitate the metabolism of arginine through iNOS have beneficial effects in cancer therapies. Macrophages utilizing iNOS as opposed to ARG exhibit an M1 phenotype and their NO secretion promotes T cell extravasion and homing against tumors. C) Adaptive immune cell subsets, including Tregs, tolerogenic DCs and MDSCs have increased IDO expression which is the enzyme responsible for metabolizing tryptophan to kynurenine. Targeting IDO activity may suppress these adaptive immune subsets within the tumor. Further reducing kynurenine accumulation in the microenvironment can ameliorate its immune suppressive effects against T cells. (iNOS, inducible nitric oxide synthase; ARG, arginase; IDO, indoleamine 2,3 dioxygenase)

Figure 4.. Manipluating fatty acid metabolism within the TME.

Increased fatty acids within a tumor microenvironment can result in accumulation of lipid droplets within immune cells or promote FAO. Immune suppressive phenotypes typically rely on FAO as a means to produce energy. Targets that inhibit CD36, the accumulation of lipid droplets, or the synthesis of FA via FASN have been found to ameliorate the FAO reliant immune suppressive metabolism. (FAO, fatty acid oxidation; FA, fatty acid; FASN, fatty acid synthase)

Figure 5.. Immune cell response to hypoxia within the tumor microenvironment.

Due to limited vasculature of a rapidly growing tumor, areas within a tumor become hypoxic which alters immune metabolism to suppressive phenotypes. Hypoxic conditions promote T regulatory stimulation and reduce effector cytokine production. Hypoxia shifts macrophages towards an M2 like phenotype, promotes MDSC suppressive function, and reduces dendritic cell stimulatory effects. However, targeting hypoxia sensing pathway, HIF, proves to be immune cell specific and results in differential effects anti-tumor therapies. (HIF, hypoxia inducible factor)