Metabolism of immune cells in cancer

Abstract

Through the successes of checkpoint blockade and adoptive cellular therapy, immunotherapy has become an established treatment modality for cancer. Cellular metabolism has emerged as a critical determinant of the viability and function of both cancer cells and immune cells. In order to sustain prodigious anabolic needs, tumours employ a specialized metabolism that differs from untransformed somatic cells. This metabolism leads to a tumour microenvironment that is commonly acidic, hypoxic and/or depleted of critical nutrients required by immune cells. In this context, tumour metabolism itself is a checkpoint that can limit immune-mediated tumour destruction. Because our understanding of immune cell metabolism and cancer metabolism has grown significantly in the past decade, we are on the cusp of being able to unravel the interaction of cancer cell metabolism and immune metabolism in therapeutically meaningful ways. Although there are metabolic processes that are seemingly fundamental to both cancer and responding immune cells, metabolic heterogeneity and plasticity may serve to distinguish the two. As such, understanding the differential metabolic requirements of the diverse cells that comprise an immune response to cancer offers an opportunity to selectively regulate immune cell function. Such a nuanced evaluation of cancer and immune metabolism can uncover metabolic vulnerabilities and therapeutic windows upon which to intervene for enhanced immunotherapy.

Fig. 1 ∣. Cancer cell metabolism and derangements in the TME.

Mitochondrial oxidation of nutrients, including glucose, amino acids and fatty acids, through the tricarboxylic acid (TCA) cycle and the electron transport chain (ETC) is a highly efficient means of producing energy for quiescent, differentiated cells. However, during periods of increased proliferation, such as after immune activation or malignant transformation, cells upregulate an alternative pathway for glucose metabolism, called aerobic glycolysis. Although less efficient in generating ATP, aerobic glycolysis allows for more rapid metabolism of glucose, efficient disposal of excess carbon and regeneration of NAD⁺ while preserving mitochondrial enzymatic activity for anabolic processes. Glycolytic intermediates are channelled through other essential pathways, such as the pentose phosphate pathway, the one-carbon pathway and the hexosamine biosynthesis pathway. These pathways support cellular processes that are critical for highly proliferative cells, such as synthesis of fatty acids and nucleic acids. Pathways for the metabolism of glutamine are also upregulated in the setting of increased proliferation. In addition to supplying the TCA cycle with carbon skeletons that maintain intermediates for biosynthesis of amino acids, nucleic acids and fatty acids (a process known as anaplerosis), glutamine is the primary source of nitrogen used for amino acid and nucleic acid synthesis. These cells also upregulate a broad range of amino acid transporters and maintain tightly controlled redox balance, primarily through NADPH synthesis. Many cells within the tumour microenvironment (TME) express ectoenzymes, such as indoleamine 2,3-dioxygenase (IDO), arginase 1 (ARG1) and CD73, which deplete nutrients, as well as increase immunosuppressive metabolites, such as kynurenine and adenosine. Along with a deranged microvasculature, these metabolic adaptations can have profound effects on the metabolic make-up of the TME, leading to depletion of vital nutrients, hypoxia, acidosis and the generation of immune-toxic metabolites as shown. MDSC, myeloid-derived suppressor cell; R-2-HG, (R)-2-hydroxyglutarate; ROS, reactive oxygen species; T_eff, effector T; T_reg, regulatory T.

Fig. 2 ∣. Metabolic derangements in the TME inhibit T cell function.

The metabolic milieu of the tumour microenvironment (TME) is a reflection of cancer metabolic programmes. Nutrient deprivation, hypoxia and toxic metabolites are conditions within the TME that confront and influence T cell metabolism and function. The consequences of TME conditions on immune cell responses can be predicted based on a growing literature of preclinical, translational and clinical studies. AMPK, AMP kinase; EZH2, enhancer of zeste homologue 2; Granz B, granzyme B; IFNγ, interferon-γ; MDSC, myeloid-derived suppressor cell; miRNA, microRNA; NFAT, nuclear factor of activated T cells; PKA, protein kinase A; R-2-HG, (R)-2-hydroxyglutarate; TCR, T cell receptor; T_eff, effector T; T_H1, T helper 1; T_mem, memory T;T_reg, regulatory T;T_scm, stem cell memory T; TNF, tumour necrosis factor.

Fig. 3 ∣. Potential metabolic targets for enhancing immune response in cancer.

Using small molecules, monoclonal antibodies and genetic editing, metabolic processes can be targeted to either disable cancer and suppressive immune cell metabolism or, conversely, engage and support effector cell metabolism. Metabolic processes in suppressive immune populations and cancer cells can be targeted to directly decrease viability, as well as to disable metabolic pathways that deplete nutrients (for example, arginase 1 (ARG1) and indoleamine 2,3-dioxygenase (IDO)), lead to toxic metabolites (for example, lactate and CD73) or induce metabolic control of effector cell populations (for example, mutant IDH1 generation of the oncometabolite (R)-2-hydroxyglutarate (R-2-HG)). Metabolic interventions may also be able to induce beneficial changes in effector populations, such as increasing longevity and antigen-specific immunologic memory. A2AR, adenosine receptor subtype A2A; AOA, amino-oxyacetic acid; 2-DG, 2-deoxyglucose; DON, 6-diazo-5-oxo-l-norleucine; ETC, electron transport chain; G6PD, glucose-6-phosphate dehydrogenase; MDSC, myeloid-derived suppressor cell; PGM3, phosphoglucomutase; TCA, tricarboxylic acid; T_eff, effector T; T_reg, regulatory T.