CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response.
Heightened effector function and prolonged persistence, the key attributes of Th1 and Th17 cells, respectively, are key features of potent anti-tumor T cells. Here, we established ex vivo culture conditions to generate hybrid Th1/17 cells, which persisted long-term in vivo while maintaining their effector function. Using transcriptomics and metabolic profiling approaches, we showed that the enhanced anti-tumor property of Th1/17 cells was dependent on the increased NAD+-dependent activity of the histone deacetylase Sirt1. Pharmacological or genetic inhibition of Sirt1 activity impaired the anti-tumor potential of Th1/17 cells. Importantly, T cells with reduced surface expression of the NADase CD38 exhibited intrinsically higher NAD+, enhanced oxidative phosphorylation, higher glutaminolysis, and altered mitochondrial dynamics that vastly improved tumor control. Lastly, blocking CD38 expression improved tumor control even when using Th0 anti-tumor T cells. Thus, strategies targeting the CD38-NAD+ axis could increase the efficacy of anti-tumor adoptive T cell therapy.
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Related Subject Headings
- Th17 Cells
- Th1 Cells
- T-Lymphocytes
- Sirtuin 1
- Neoplasms
- NAD
- Mice, Inbred C57BL
- Immunotherapy
- Glutamine
- Forkhead Box Protein O1
Citation
Published In
DOI
EISSN
ISSN
Publication Date
Volume
Issue
Start / End Page
Related Subject Headings
- Th17 Cells
- Th1 Cells
- T-Lymphocytes
- Sirtuin 1
- Neoplasms
- NAD
- Mice, Inbred C57BL
- Immunotherapy
- Glutamine
- Forkhead Box Protein O1