CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response. Cell Metab 2018 Jan 09;27(1):85-100.e8
Date
11/14/2017Pubmed ID
29129787Pubmed Central ID
PMC5837048DOI
10.1016/j.cmet.2017.10.006Scopus ID
2-s2.0-85033367546 (requires institutional sign-in at Scopus site) 171 CitationsAbstract
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.
Author List
Chatterjee S, Daenthanasanmak A, Chakraborty P, Wyatt MW, Dhar P, Selvam SP, Fu J, Zhang J, Nguyen H, Kang I, Toth K, Al-Homrani M, Husain M, Beeson G, Ball L, Helke K, Husain S, Garrett-Mayer E, Hardiman G, Mehrotra M, Nishimura MI, Beeson CC, Bupp MG, Wu J, Ogretmen B, Paulos CM, Rathmell J, Yu XZ, Mehrotra SAuthor
Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
ADP-ribosyl Cyclase 1Animals
Forkhead Box Protein O1
Glutamine
Immunotherapy
Mice, Inbred C57BL
NAD
Neoplasms
Sirtuin 1
T-Lymphocytes
Th1 Cells
Th17 Cells
