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

Shilpak Chatterjee, Anusara Daenthanasanmak, Paramita Chakraborty, Megan W. Wyatt, Payal Dhar, Shanmugam Panneer Selvam, Jianing Fu, Jinyu Zhang, Hung Nguyen, Inhong Kang, Kyle Toth, Mazen Al-Homrani, Mahvash Husain, Gyda Beeson, Lauren Ball, Kristi Helke, Shahid Husain, Elizabeth Garrett-Mayer, Gary Hardiman, Meenal MehrotraMichael I. Nishimura, Craig C. Beeson, Melanie Gubbels Bupp, Jennifer Wu, Besim Ogretmen, Chrystal M. Paulos, Jeffery Rathmell, Xue Zhong Yu, Shikhar Mehrotra*

*Corresponding author for this work

Research output: Contribution to journalArticle

54 Citations (Scopus)
1 Downloads (Pure)

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. Chatterjee et al. show that intracellular NAD + levels control the anti-tumor potential of hybrid Th1/17 cells through the NAD + -Sirt1-Foxo1 axis. Expression of the NADase CD38 inversely correlates with NAD+ levels and regulates anti-tumor T cell response. Genetic ablation or antibody-mediated targeting of CD38 on T cells improves tumor control.

Original languageEnglish
Pages (from-to)85-100.e8
JournalCell metabolism
Volume27
Issue number1
Early online date09 Nov 2017
DOIs
Publication statusPublished - 09 Jan 2018
Externally publishedYes

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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