Targeting oncometabolism to maximize immunotherapy in malignant brain tumors

Abstract

Brain tumors result in significant morbidity and mortality in both children and adults. Recent data indicate that immunotherapies may offer a survival benefit after standard of care has failed for malignant brain tumors. Modest results from several late phase clinical trials, however, underscore the need for more refined, comprehensive strategies that incorporate new mechanistic and pharmacologic knowledge. Recently, oncometabolism has emerged as an adjunct modality for combinatorial treatment approaches necessitated by the aggressive, refractory nature of high-grade glioma and other progressive malignant brain tumors. Manipulation of metabolic processes in cancer and immune cells that comprise the tumor microenvironment through controlled targeting of oncogenic pathways may be utilized to maximize the efficacy of immunotherapy and improve patient outcomes. Herein, we summarize preclinical and early phase clinical trial research of oncometabolism-based therapeutics that may augment immunotherapy by exploiting the biochemical and genetic underpinnings of brain tumors. We also examine metabolic pathways related to immune cells that target tumor cells, termed "tumor immunometabolism". Specifically, we focus on glycolysis and altered glucose metabolism, including glucose transporters, hexokinase, pyruvate dehydrogenase, and lactate dehydrogenase, glutamine, and we discuss targeting arginase, adenosine, and indoleamine 2,3-dioxygenase, and toll-like receptors. Lastly, we summarize future directions targeting metabolism in combination with emerging therapies such as oncolytic virotherapy, vaccines, and chimeric antigen receptor T cells.

Figure 1.

Metabolic interaction between glioma cells, T cells, and myeloid-derived suppressor cells (MDSCs). Glioma cells uptake nutrients from the extracellular space, which include glucose, glutamine, amino acids, acetate, and fatty acids (FAs) and use these nutrients to compensate for increased energy demands (e.g., high glycolytic rate). This leads to a metabolic competition with other cell types within the microenvironment (e.g., T cells), which become significantly affected by the lack of key nutrients (e.g., glucose and glutamine). Glioma cells metabolize tryptophan to the immunosuppressive molecule kynurenine via (Indoleamine 2,3-Dioxygenase 1 (IDO1). Furthermore, the increased release of lactate and succinate from the glioma, leads to both T cell suppression and MDSC polarization towards an anti-inflammatory phenotype. Polarized MDSCs reduce the extracellular levels of L-arginine, release nitric oxide (NO), and express the programmed death-ligand 1 (PD-L1), further inhibiting T cell anti-tumor responses. Other abbreviations: α-KG (α -ketoglutarate), programmed cell death protein 1 (PD-1), Nicotinamide adenine dinucleotide + (NAD+), lactate dehydrogenase (LDH), alanine, serine, cysteine transporter 2 (ASCT2), succinate receptor 1 (SUCNR1), arginase 1 (ARG1), monocarboxylate transporter (MCT), glucose transporter (GLUT) and fatty acid oxidation (FAO).

Figure 2.

Targeting tumor metabolism in gliomas with biologics and small molecule inhibitors. Cell metabolism and the availability of metabolic substrates in the glioma microenvironment is dependent on the activity of multiple cell types, including myeloid-derived suppressor cells (MDSCs), tumor associate macrophages (TAMs), glioma cells, and T cells. Inhibitors (in red) and agonists (in green) aimed at interfering with specific targets (blue) of this complex metabolic network have been developed and are under clinical testing. These include (i) inhibitors that act on altered glucose and lactate metabolism in gliomas [such as 3-brompyruvate (3-BrPA), dichloroacetate (DCA) and AZD3965]; (ii) inhibitors of other metabolic enzymes in glioma [such as isocitrate dehydrogenases (IDH) 1–2 via ivosidenib (AG-120) and vorasidenib (AG-881), glutaminase (GLS1) via CB-839, fatty acid synthase (FASN) via TVB-2640, and indoleamine 2,3-dioxygenase (IDO)1 via indoximod (1-MT) and epacadostat (INCB024360)]; (iii) inhibitors of arginase (ARG) 1 in TAM via molecules such as CB-1158; and (iv) modulators of membrane bound proteins [such as the 5′-nucleotidase CD73 via α, β-methylene ADP (APCP), and the toll like receptors (TLRs) 3–7/8 via the agonists poly (I:C) stabilized by lysine (poly-ICLC) and MEDI9197]. Oval inserts/bubbles show how current and/or future combination of immunotherapies and chemotherapies can be used to overcome certain metabolic alterations of the glioma. These include the use of α_vβ₃ antagonists to target glioma cells overexpressing GLUT3, LDH inhibitors (e.g., NCI-006) to target the overexpression of lactate dehydrogenase (LDH), bevacizumab (VEGF inhibitor) in combination with epacadostat (IDO inhibitor), PD-1 inhibitors that are used in synergy with APCP, AB-881, and CB-1158 treatments, and finally the combination of temozolomide (TMZ) with TLR inhibitors and HK2 inhibitors (the latter being able to significantly enhance the efficacy of TMZ treatment). Other abbreviations: FA (fatty acids), α-KG (α -ketoglutarate), 2-HG (2-hydroxyglutarate), GSH (glutathione), adenosine monophosphate (AMP), Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1).