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Nicotinamide Riboside Enhances Adoptive T Cell Therapy by Promoting Memory Differentiation and Metabolic Fitness

ABSTRACT: Enhancing the efficacy of adoptively transferred T cells is essential for successful immunotherapy. The cytotoxic activity of these T cells is closely related to their mitochondrial function, which plays a critical role in T cell differentiation. This study explored the potential of nicotinamide riboside (NR), known to enhance mitochondrial function, to improve the efficacy of adoptively transferred CD8+ T cells against hepatocellular carcinoma (HCC). In subcutaneous and metastatic HCC tumor models, NR treatment significantly improved the effectiveness of adoptive T-cell therapy (ACT). NR promoted the differentiation of CD44hiCD62Lhi central memory T cells (TCM) and upregulated memory-associated genes (Tcf7, Ccr7, and Foxo1). Upon restimulation, NR-treated CD8+ T cells exhibited strong recall responses, as evidenced by metabolic reprogramming and increased cytokine production. Furthermore, RNA sequencing revealed an increased expression of Foxo1 and its target genes. Inhibition of Foxo1 partially reversed the beneficial effects of NR on mitochondrial fitness and cytotoxic function, suggesting a role for Foxo1-associated pathways in mediating these effects. In summary, NR improved mitochondrial fitness and promoted TCM differentiation, in part through a transcriptional program associated with Foxo1, thereby improving the efficacy of adoptive T-cell therapy. These findings identify NR as a promising and translatable metabolic adjuvant for HCC immunotherapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE335269 | GEO | 2026/06/19

REPOSITORIES: GEO

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Project description:Adoptive immunotherapy using ex vivo expanded tumor reactive lymphocytes can mediate durable cancer regression in selected melanoma patients. Analyses of these trials have associated the in vivo engraftment ability of the transferred cells with their anti-tumor efficacy. Thus, there is significant clinical interest in the prospective isolation of tumor specific T cells that can reliably persist after transfer. Animal studies have suggested that central memory CD8+ T cells (TCM) have divergent capabilities including effector differentiation to target antigen and stem cell-like self renewal that enable long term survival after adoptive transfer. In this study, we sought to isolate human melanoma specific TCM to define their in vivo fate and function after autologous therapeutic transfer to metastatic patients. To facilitate the high throughput identification of these rare cells from patients, we report that TCM have a defined stoichiometric production of IL-2 and IFN-g mRNA after antigen stimulation. Melanoma specific T cells screened for high relative IL-2 production possessed a TCM phenotype and superior in vitro proliferative capacity compared to cells with low IL-2 production. To investigate in vivo effector function and self renewal capability, melanoma specific TCM underwent in vitro expansion and differentiation into lytic effector clones and then were adoptively transferred back into their hosts. These clones targeted skin melanocytes in all five patients and persisted long term and reacquired parental TCM attributes in four patients after transfer. These findings demonstrate the favorable engraftment fitness for human TCM-derived clones, but further efforts to improve their anti-tumor efficacy are still necessary. We used microarrays to compare the resting gene expression profile of melanoma specific CD8+ T cell clones that were derived from either High IL-2:IFN index precursors or Low IL-2:IFN index precursors. Three melanoma specific effector clones were derived from parental cells that possessed a high IL-2:IFN index from three independent patients with metastatic melanoma. Two melanoma specific effector clones were derived from parental cells that possessed a low IL-2:IFN index from two independent patients with metastatic melanoma. We used microarrays to compare the resting gene expression profile of the CD8+ T cell clones that were derived from either high IL-2:IFN index precursors or low IL-2:IFN index precursors.

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Nicotinamide Riboside Enhances Adoptive T Cell Therapy by Promoting Memory Differentiation and Metabolic Fitness

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