Targeting metabolism to improve CAR-T cells therapeutic efficacy

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy achieved advanced progress in the treatment of hematological tumors. However, the application of CAR-T cell therapy for solid tumors still faces many challenges. Competition with tumor cells for metabolic resources in an already nutrient-poor tumor microenvironment is a major contributing cause to CAR-T cell therapy's low effectiveness. Abnormal metabolic processes are now acknowledged to shape the tumor microenvironment, which is characterized by increased interstitial fluid pressure, low pH level, hypoxia, accumulation of immunosuppressive metabolites, and mitochondrial dysfunction. These factors are important contributors to restriction of T cell proliferation, cytokine release, and suppression of tumor cell-killing ability. This review provides an overview of how different metabolites regulate T cell activity, analyzes the current dilemmas, and proposes key strategies to reestablish the CAR-T cell therapy's effectiveness through targeting metabolism, with the aim of providing new strategies to surmount the obstacle in the way of solid tumor CAR-T cell treatment.

Figure 1

T cell metabolic crosstalk in TME. In the tumor microenvironment, TCR complex and co-receptor CD28 receive stimuli that activate T cells. GLUT1 expression is upregulated, glucose is lacking in the tumor microenvironment, lactate content is high, and the cells are in an acidic environment. NAD+-dependent deacetylase (Sirt2) inhibits T cell function, lipid accumulation increases, and CD36 expression is upregulated. Cholesterol accumulation induces the expression of immune checkpoints. eATP promotes Ca+ in the cytoplasm and then enhances the mitochondrial activity. LDHA catalyzes 2-oxoglutarate to S-2HG under hypoxia to regulate T cells proliferation. Increased levels of Fe2+ results in lipid peroxidation, which induces ferroptosis. Cu+ can bind to the lipoyl protein in TCA and promote abnormal oligomerization of the lipoyl protein. Increasing potassium levels cause an elevation in the total cellular AcCoA. ACC: Acetyl-CoA carboxylase; AcCoA: Acetyl-coenzyme A; ACSS 1: Acyl-CoA synthetase short chain family member 1; CoA: Coenzyme A; CPT1a: Carnitine palmitoyl-transferase 1A; eATP: Extracellular adenosine 5’-triphosphate; ER: Endoplasmic reticulum; FABP: Fatty acid-binding protein; FAO: Fatty acid oxidation; FASN: Fatty acid synthase; GLUT: Glucose transporter; HIF: Hypoxia inducible factor-1; LAG-3: Lymphocyte activation gene 3; LCFA: Long-chain fatty acids; LDH: Lactate dehydrogenase; LDL: Low density lipoprotein; LDLR: Low density lipoprotein receptor; LDHA: Lactate dehydrogenase A; MCT: Medium-chain triglyceride; NAD: Nicotinamide adenine dinucleotide; OxLDL: Oxidized low-density lipoprotein; PD-1: Programmed death 1; PDC: Pyruvate dehydrogenase complex; S-2HG: S-2-hydroxyglutarate; TCA: Tricarboxylic acid cycle; TCR: T cell receptor; TIM-3: T cell immunoglobulin domain and mucin domain-3; TME: Tumor microenvironment.

Figure 2

Metabolic interventions for improving CAR-T cells efficacy in TME. 4-1BB co-stimulation signaling or AMPK or PGC1α agonist activate PGC1α-NRF1/2 and Notch/FOXM1 signaling to facilitate mitochondrial biogenesis and OXPHOS to increase mitochondrial stemness leading to T_SCM population elevation. Treatment with the inhibitors of PI3K or mTORC or MEK or AKT activator metformin could also promote FAO and TCA cycle to increase mitochondrial biogenesis. Blocking the binding of β2-AR and Nor-adrenaline could also increase mitochondrial biogenesis. Cytokines such as IL-15, IL-7 and IL-21 could also accelerate FAO and OXPHOS rate. Inhibition of IDO with the vaccine or Flu+Cy or epacadost or overexpression of miR153 could increase tryptophan and restore the activity of CAR-T cells. Treatment with CD39 or CD73 inhibitors could prevent conversion of ATP/ADP to AMP and INO and further block the binding of INO to A2AR expressed on CAR-T cells. Blockade of A2AR using genetic shRNA or CRISPR/Cas9, or distinct antagonists enhanced the anti-tumor efficiency of CAR-T cells. A2AR: A2A receptor; ADO: Adenosine; ADP: Adenosine 5’-diphosphate; AKT: Protein kinase B; AMP: Adenosine monophosphate; AMPK: AMP-activated protein kinase; ATP: Adenosine 5’-triphosphate; β2-AR: β2-adrenergic receptor; CAR: Chimeric antigen receptor; Cy: Cyclophosphamide; FAO: Fatty acid oxidation; Flu: Fludarabine; FOXM1: Forkhead box M1; IDO: Indoleamine-2,3-dioxygenase; IL: Interleukin; INO: Inosine; KYN: Kynurenine; MAPK: Mitogen-activated protein kinase; MEK: Mitogen-activated extracellular signal-regulated kinase; miR: MicroRNA; mTORC: Mechanistic target of rapamycin complex; NRF: Nuclear factor erythroid 2-related factor; OXPHOS: Oxidative phosphorylation; PD1: Programmed death 1; PGC1α: Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α; PI3K: Phosphoinositide 3-kinase; shRNA: Short hairpin RNA; TCA: Tricarboxylic acid cycle; TME: Tumor microenvironment; Tscm: Stem cell-like memory T cell.