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Competitive glucose metabolism as a target to boost bladder cancer immunotherapy

Abstract

Bladder cancer — the tenth most frequent cancer worldwide — has a heterogeneous natural history and clinical behaviour. The predominant histological subtype, urothelial bladder carcinoma, is characterized by high recurrence rates, progression and both primary and acquired resistance to platinum-based therapy, which impose a considerable economic burden on health-care systems and have substantial effects on the quality of life and the overall outcomes of patients with bladder cancer. The incidence of urothelial tumours is increasing owing to population growth and ageing, so novel therapeutic options are vital. Based on work by The Cancer Genome Atlas project, which has identified targetable vulnerabilities in bladder cancer, immune checkpoint inhibitors (ICIs) have arisen as an effective alternative for managing advanced disease. However, although ICIs have shown durable responses in a subset of patients with bladder cancer, the overall response rate is only ~15–25%, which increases the demand for biomarkers of response and therapeutic strategies that can overcome resistance to ICIs. In ICI non-responders, cancer cells use effective mechanisms to evade immune cell antitumour activity; the overlapping Warburg effect machinery of cancer and immune cells is a putative determinant of the immunosuppressive phenotype in bladder cancer. This energetic interplay between tumour and immune cells leads to metabolic competition in the tumour ecosystem, limiting nutrient availability and leading to microenvironmental acidosis, which hinders immune cell function. Thus, molecular hallmarks of cancer cell metabolism are potential therapeutic targets, not only to eliminate malignant cells but also to boost the efficacy of immunotherapy. In this sense, integrating the targeting of tumour metabolism into immunotherapy design seems a rational approach to improve the therapeutic efficacy of ICIs.

Key points

  • Immune checkpoint inhibitors (ICIs) can effectively treat advanced bladder cancer in a subset of patients, but overall response is low due to a high rate of primary or acquired resistance.

  • The metabolic phenotype of bladder cancer cells is heterogeneous and distinct from their normal-tissue counterparts, as cancer cells are avid for nutrients, especially glucose.

  • An overlapping metabolic phenotype exists between cancer cells and activated T cells, leading to metabolic competition that limits nutrient availability, increases microenvironmental acidosis and impairs the immune function of T cells.

  • Numerous inhibitors of glucose metabolism have been shown to be effective in eliminating cancer cells that overexpress the glycolysis-related target.

  • Integrating targeting of bladder cancer metabolism into immunotherapy design seems a rational approach to improve the therapeutic efficacy of ICIs.

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Fig. 1: Molecular subtypes of urothelial bladder cancer, based on genomic and transcriptional features, and prognostic associations.
Fig. 2: Mechanism of action of immune checkpoints and their targeted blockade.
Fig. 3: The metabolic pathway of glycolysis.
Fig. 4: Reprogramming of glucose metabolism in urothelial bladder cancer.
Fig. 5: The tumour immunity cycle.
Fig. 6: Distinct metabolic programmes of quiescent T cells, activated CD8+ T cells and memory CD8+ T cells.
Fig. 7: Metabolic competition between cancer and cytotoxic T cells in the tumour microenvironment.

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Acknowledgements

This work was developed under the scope of the project NORTE-01-0145-FEDER- 000013, supported by the Northern Portugal Regional Operational Programme (NORTE 2020) under the Portugal Partnership Agreement, through the European Regional Development Fund (FEDER), and through the Competitiveness Factors Operational Programme (COMPETE) and by national funds, through the Foundation for Science and Technology (FCT), under the scope of the project POCI-01–0145-FEDER-007038. J.A. received a fellowship from FCT, ref. SFRH/BPD/116784/2016.

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J.A. and L.L.S. researched data for the article. F.B. and J.A. wrote the manuscript. All authors made substantial contributions to discussions of content and the review and editing of the manuscript before submission.

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Correspondence to Fátima Baltazar.

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Nature Reviews Urology thanks N. Pavlova and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Non-muscle-invasive bladder cancer

(NMIBC). Cancer that can reach the urothelium (pathological stages Tis and Ta) or the lamina propria (pathological stage T1), but does not invade the muscularis propria.

Muscle-invasive bladder cancer

(MIBC). Cancer that invades the muscularis propria (pathological stages ≥T2).

The Cancer Genome Atlas (TCGA) project

Joint programme between the National Cancer Institute and the National Human Genome Research Institute, comprising genomic, epigenomic, transcriptomic and proteomic data from over 20,000 primary cancers and matched normal samples, including 33 cancer types; information is publicly available to the research community.

Umbrella trials

Clinical protocols where all patients (and all subtrials) share a common tumour type, the ‘umbrella’.

B7 family

Peripheral membrane proteins found on activated antigen-presenting cells that play an important role in the regulation of T cell activity. Depending on the protein they interact with on T cells, they can produce costimulatory or coinhibitory signals. The B7 family comprises ten members: CD80 (or B7.1), CD86 (or B7.2), B7-H1 (or PD-L1 or CD274), B7-DC (or PD-L2 or CD273), B7-H2 (or ICOSL), B7-H3 (or CD276), B7-H4 (or B7S1, B7x, or Vtcn1), B7-H5 (or VISTA, GI24, Dies1 or PD-1H), B7-H6 (or NCR3LG1) and B7-H7 (or HHLA2).

Glucose addiction

Driven by oncogenic gene mutations or other alterations, cancer cells displaying this metabolic phenotype prefer glycolysis over oxidative phosphorylation for energy production, and convert part of the consumed glucose into lactic acid. Lactic acid contributes to acidification of the tumour microenvironment and is associated with various cancer aggressiveness features, including angiogenesis, invasion and immune escape.

18F-fluorodeoxyglucose PET

(18F-FDG–PET). Imaging tool that detects increased glucose uptake and glycolysis through 2-deoxy-2-[18F]fluoro-d-glucose. By allowing quantification of the rate of 18F-FDG uptake, it is a useful tool for monitoring disease activity and response to therapy of glucose-avid cancers.

SLC16 gene family

Gene family with 14 members, of which four encode the monocarboxylate transporters MCT1 (SLC16A1), MCT2 (SLC16A7), MCT3 (SLC16A8) and MCT4 (SLC16A3), proton symporters that mediate the transport of monocarboxylates such as l-lactate, pyruvate and ketone bodies across the plasma membrane. SLC16A2 encodes the thyroid hormone transporter MCT8 and SLC16A10 the aromatic amino acid transporter TAT1. The function of the remaining eight SLC16A members is still unknown.

Cancer immunogram

Comprehensive framework of seven tumour parameter classes (tumour foreignness, tumour sensitivity to immune effectors, absence of inhibitory tumour metabolism, absence of soluble inhibitors, absence of checkpoints, immune cell infiltration, and general immune status), describing the different interactions between cancer cells and the immune system, with the aim of providing a better understanding of the response of patients to immunotherapy.

Symporters

Membrane proteins that co-transport molecules across the cell membrane in the same direction.

Dual-track pathway of bladder carcinogenesis

Postulates that bladder cancer develops via two distinct but overlapping pathways, resulting in the two main phenotypic variants — papillary and non-papillary — with distinct biological behaviours and prognoses.

Pharmacokinetics

Process by which the body deals with a specific drug/xenobiotic after administration, involving the mechanisms of absorption, distribution, metabolic changes and routes of excretion.

Combination index

Index to assess synergy between two drugs. Combination index (CI) = 1 denotes additivity, CI > 1 denotes antagonism, CI < 1 denotes synergism.

Molecular docking

Tool that uses structural molecular biology and computer-assisted drug design to predict the principal binding mode(s) of a ligand to a protein of known three-dimensional structure.

N-Acetyltransferase

Enzyme that catalyses the acetylation (transfer of acetyl group from acetyl coenzyme A) of compounds such as arylamines, arylhydroxylamines and arylhydrazines.

TRAIL

Cytokine produced by most normal tissues that induces apoptosis by binding to death receptors DR4 (TRAIL-RI) and DR5 (TRAIL-RII), by a caspase 8-dependent process.

Cancer chronotherapy

Temporal adjustments made to the administration schedule of drugs, aiming to reduce drug cytotoxicity.

Bicarbonate therapy

Sodium bicarbonate administration to increase the extracellular pH and counteract the tumour acidity.

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Afonso, J., Santos, L.L., Longatto-Filho, A. et al. Competitive glucose metabolism as a target to boost bladder cancer immunotherapy. Nat Rev Urol 17, 77–106 (2020). https://doi.org/10.1038/s41585-019-0263-6

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