713 Vitamin B6-mediated lipid metabolic reprogramming as a strategy to restore antitumor T cell immunity in aging
Year: 2026
Type: conference-abstract
Abstract: Background With global population aging, older adults are projected to account for 14 million new cancer cases by 2035, but how aging impairs antitumor T cell immunity remains poorly understood. 1 Adoptive T cell therapies, particularly chimeric antigen receptor (CAR) T cells, have transformed cancer treatment, yet their efficacy declines with patient age, largely due to reduced fitness of the infused T cells.2 High-quality CAR-T cells are enriched for stem-like phenotypes that sustain expansion and durable tumor control, and central memory T cells (Tcm) are especially critical but develop immunosenescence-associated defects.3–5 Tcm rely on fatty acid (FA)–driven oxidative phosphorylation, and vitamin B6 promotes lipid mobilization for FA oxidation in non-immune tissues.6 7 We found that aged murine Tcm exhibit a marked depletion of vitamin B6, leading us to hypothesize that vitamin B6 supplementation could correct age-associated lipid metabolic defects in T cells, particularly Tcm, thereby improving CAR-T cell quality.Methods We performed multi-omic profiling of young and old murine T cm to define age-related metabolic remodeling and analyzed transcriptomic data from young and aged donors and from CAR-T cell–treated patients to assess clinical relevance.3 8 Ex vivo, murine and human T cells from young and aged donors were treated with vitamin B6 and evaluated for FA mobilization, mitochondrial fitness, differentiation state, and exhaustion under chronic stimulation. Antitumor function was assessed in vivo in two models, with or without vitamin B6 supplementation, by transferring (1) young and aged gp33-specific Tcm and (2) HER2-directed CAR-T cells from young and old mice.Results Aged murine T cm showed profound lipidomic remodeling (figure 1), defective FA oxidation, reduced mitochondrial fitness, and loss of stem-like properties. Human Tcm displayed conserved age-associated defects in lipid metabolism, and CAR-T cells from non-responder patients expressed lower levels of lipid metabolism-related genes. Vitamin B6 supplementation enhanced lipid mobilization, mitochondrial respiration, promoted stem-like properties, and attenuated exhaustion under chronic stimulation in aged Tcm cells. In vivo, vitamin B6 improved antitumor immunity by increasing T cell persistence and delaying tumor growth (figure 2), and in aged human T cells it rescued mitochondrial fitness and stemness-associated features.Conclusions In conclusion, vitamin B6-driven lipid metabolic reprogramming rejuvenates aged T cells by restoring stem-like features, reducing exhaustion, and boosting antitumor activity—benefiting the entire T cell compartment, and especially T cm cells. These data support vitamin B6 supplementation as a clinically translatable strategy to improve CAR-T cell fitness, persistence, and efficacy in older cancer patients.Acknowledgements We gratefully acknowledge the financial support from the Swiss National Science Foundation (SNSF), which made this work possible. We also thank the Metabolomics Unit of the University of Lausanne (UNIL) for their valuable technical support and expertise in metabolomic analyses. In addition, we acknowledge the FACS facility of the University of Fribourg (UNIFR) for their assistance with cytometry data acquisition and analysis, as well as the UNIFR animal facility for excellent animal care and experimental support.References Pilleron S, Sarfati D, Janssen-Heijnen M, Vignat J, Ferlay J, Bray F, et al. Global cancer incidence in older adults, 2012 and 2035: a population-based study. Int J Cancer. 2019;144(1):49–58. doi:10.1002/ijc.31664.Quan XQ, Ruan L, Zhou HR, Gao WL, Zhang Q, Zhang CT. Age-related changes in peripheral T-cell subpopulations in elderly individuals: An observational study. Open Life Sci. 2023 Jan 1;18(1). doi:10.1515/biol-2022-0557.Fraietta JA, Lacey SF, Orlando EJ, Pruteanu-Malinici I, Gohil M, Lundh S, et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018 May;24(5):563–71. doi:10.1038/s41591-018-0010-1.Noll JH, Levine BL, June CH, Fraietta JA. 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Nat Commun. 2022 Sep 1;13(1):5128. doi:10.1038/s41467-022-32869-x PubMed PMID: 36050300; PubMed Central PMCID: PMC9436929.Ethics Approval All animal experiments were performed in the animal facility at the University of Fribourg (UNIFR), as approved by the veterinary authorities of the canton of Fribourg and performed in accordance with Swiss federal law (VD3572), approval number 38124. Patient samples were obtained in collaboration with the Swiss CRS Transfusion Interrégionale.Abstract 713 Figure 1Lipidomic analysis of aged Tcm reveals a marked reduction in cholesterol and phosphatidylcholine, alongside accumulation of triglycerides, ceramides, sphingomyelins, and lysophosphatidylcholine, among other lipid speciesAbstract 713 Figure 2Vitamin B6 supplementation enhances anti-tumor function of aged central memory T cells. Vitamin B6 supplementation of aged Tcm p14 cells improves long-term tumor control, reaching performance comparable to that of young Tcm p14 cells
Institution: University of Fribourg
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W7225311331