Methionine regulates the antitumor function of CD8+ T cells through polyamine synthesis
| dc.contributor.author | Zhao, Tian | |
| dc.contributor.supervisor | Lum, Julian J. | |
| dc.date.accessioned | 2026-01-28T21:28:24Z | |
| dc.date.available | 2026-01-28T21:28:24Z | |
| dc.date.issued | 2026 | |
| dc.degree.department | Department of Biochemistry and Microbiology | |
| dc.degree.level | Doctor of Philosophy PhD | |
| dc.description.abstract | As an essential amino acid, methionine (Met) is critical for T cell activation. While methionine restriction (MR) combined with immune checkpoint blockade has been shown to enhance T cell function, the impact of Met on adoptive T cell therapies is unknown. Here, we examined the functionality of T cells under MR and methionine cycle inhibition (MAT2Ai) using in vitro models and a murine adoptive T cell therapy model. In vitro, transient MR or MAT2Ai increased interferon gamma (IFNγ) expression in CD8+ T cells, whereas prolonged MR or MAT2Ai led to the upregulation of T cell exhaustion-associated markers. Mechanistically, transient MR suppressed the polyamine synthesis pathway, and genetic ablation of a key gene in this pathway resembles the effect of MR on gamma (IFNγ) expression, indicating that transient MR enhanced T cell function by inhibiting polyamine synthesis. Despite this, pre-infusion transient MR of ovalbumin (OVA)-specific (OT-I) CD8+ T cells had no measurable impact on antitumor efficacy against EG7-OVA tumors in vivo. In contrast, an MR diet reduced intertumoral Met levels and promoted EG7-OVA tumor growth in mice treated with OT-I T cells, thereby confirming that Met is essential for the activity of adoptively transferred T cells. Collectively, these findings suggest that enhancing Met availability in the tumor microenvironment may improve the efficacy of adoptive T cell therapies. | |
| dc.description.scholarlevel | Graduate | |
| dc.identifier.bibliographicCitation | Zhao, T., Carleton, G.A., Macpherson, S., Shiyuk, M., Monaghan, J., Han, J., Uchenunu, O., Rottapel, R., DeBerardinis, R.J., Stewart, K.M., et al. (2025). Methionine regulates antitumor function of CD8(+) T cells through polyamine synthesis. bioRxiv. 10.1101/2025.10.03.680201. | |
| dc.identifier.bibliographicCitation | Zhao, T., and Lum, J.J. (2022). Methionine cycle-dependent regulation of T cells in cancer immunity. Front Oncol 12, 969563. 10.3389/fonc.2022.969563. | |
| dc.identifier.uri | https://hdl.handle.net/1828/23081 | |
| dc.language | English | eng |
| dc.language.iso | en | |
| dc.rights | Available to the World Wide Web | |
| dc.subject | T cell metabolism | |
| dc.subject | Cancer immunology | |
| dc.title | Methionine regulates the antitumor function of CD8+ T cells through polyamine synthesis | |
| dc.type | Thesis |