Cell Metabolism
Volume 27, Issue 1, 9 January 2018, Pages 85-100.e8
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Article
CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

https://doi.org/10.1016/j.cmet.2017.10.006Get rights and content
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Highlights

  • Th1/17 cells with effector and stemness features exhibit durable tumor control

  • High glutaminolysis of Th1/17 cell regulates its viability and anti-tumor response

  • NAD+-Sirt1-Foxo1 axis is central to the anti-tumor phenotype of Th1/17 cells

  • Targeting NADase CD38 on T cells increases NAD+ levels and controls tumor growth

Summary

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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