CD38-NAD + Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response

Cell Metab. 2018 Jan 9;27(1):85-100.e8. doi: 10.1016/j.cmet.2017.10.006. Epub 2017 Nov 9.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • ADP-ribosyl Cyclase 1 / metabolism*
  • Animals
  • Forkhead Box Protein O1 / metabolism
  • Glutamine / metabolism
  • Immunotherapy*
  • Mice, Inbred C57BL
  • NAD / metabolism*
  • Neoplasms / immunology*
  • Neoplasms / metabolism
  • Neoplasms / therapy*
  • Sirtuin 1 / metabolism
  • T-Lymphocytes / immunology*
  • Th1 Cells / immunology
  • Th17 Cells / immunology

Substances

  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Glutamine
  • NAD
  • ADP-ribosyl Cyclase 1
  • Sirtuin 1