Metabolic dialogues: regulators of chimeric antigen receptor T cell function in the tumor microenvironment

• Published in: Molecular oncology Vol. 18; no. 7; pp. 1695 - 1718
• Main Authors: Moraly, Josquin, Kondo, Taisuke, Benzaoui, Mehdi, DuSold, Justyn, Talluri, Sohan, Pouzolles, Marie C., Chien, Christopher, Dardalhon, Valérie, Taylor, Naomi
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.07.2024; FEBS Press; John Wiley and Sons Inc; Wiley
• Subjects: Adenosine triphosphate; Animals; Antigens; anti‐tumor immunotherapy; Cell death; Cell differentiation; Cell surface; Chemokines; chimeric antigen receptor; Chimeric antigen receptors; Dehydrogenases; Disease management; Enzymes; Epidermal growth factor; Epigenetics; Fatty acids; Glucose; Good Manufacturing Practice; Humans; Hypoxia; immunometabolism; Immunotherapy; Immunotherapy, Adoptive - methods; Kinases; Life Sciences; Ligands; Lymphocytes; Lymphocytes T; Malignancy; Melanoma; Metabolic pathways; Metabolism; Metabolites; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Neoplasms - therapy; Nutrient availability; nutrient transporters; Oxidation; Phosphorylation; Polyamines; Post-translation; Proteins; Receptors, Chimeric Antigen - immunology; Receptors, Chimeric Antigen - metabolism; Review; T cell receptors; T Cells; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; Transcription factors; Translation; Tumor Immunology; Tumor Microenvironment; Tumor Microenvironment - immunology; Tumor-infiltrating lymphocytes; T cells; T cells; chimeric antigen receptor; nutrient transporters; tumor microenvironment; immunometabolism; anti‐tumor immunotherapy
• ISSN: 1574-7891; 1878-0261; 1878-0261
• DOI: 10.1002/1878-0261.13691

Tumor‐infiltrating lymphocytes (TILs) and chimeric antigen receptor (CAR) T cells have demonstrated remarkable success in the treatment of relapsed/refractory melanoma and hematological malignancies, respectively. These treatments have marked a pivotal shift in cancer management. However, as “living drugs,” their effectiveness is dependent on their ability to proliferate and persist in patients. Recent studies indicate that the mechanisms regulating these crucial functions, as well as the T cell's differentiation state, are conditioned by metabolic shifts and the distinct utilization of metabolic pathways. These metabolic shifts, conditioned by nutrient availability as well as cell surface expression of metabolite transporters, are coupled to signaling pathways and the epigenetic landscape of the cell, modulating transcriptional, translational, and post‐translational profiles. In this review, we discuss the processes underlying the metabolic remodeling of activated T cells, the impact of a tumor metabolic environment on T cell function, and potential metabolic‐based strategies to enhance T cell immunotherapy. T cells engineered to express chimeric antigen receptors (CAR) are dependent on the transport and utilization of nutrients from the extracellular space, fueling their anti‐tumor activity. Nonetheless, the tumor microenvironment is characterized by a dearth of several key nutrients and alterations in metabolic scavenging systems. It is therefore critical to equip CAR T cells to optimally function in these unique environments.