Authors: | Chatterjee, S; Daenthanasanmak, A.; Chakraborty, P.; Wyatt, M. W.; Dhar, P.; Selvam, S. P.; 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, M. I.; Beeson, C. C.; Bupp, M. G.; Wu, J; Ogretmen, B.; Paulos, C. M.; Rathmell, J.; Yu, X. Z.; Mehrotra, S |
Article Title: | CD38-NAD(+)Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response |
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. |
Journal Title: | Cell metabolism |
Volume: | 27 |
Issue: | 1 |
ISSN: | 1932-7420; 1550-4131 |
Publisher: | Elsevier Inc |
Journal Place: | United States |
Date Published: | 2018 |
Start Page: | 85 |
End Page: | 100.e8 |
Language: | eng |
DOI/URL: |
S1550-4131(17)30618-6 |
Notes: | LR: 20180309; CI: Copyright (c) 2017; GR: R21 CA137725/CA/NCI NIH HHS/United States; GR: R01 CA138930/CA/NCI NIH HHS/United States; GR: P30 CA138313/CA/NCI NIH HHS/United States; GR: P01 CA203628/CA/NCI NIH HHS/United States; GR: P01 CA154778/CA/NCI NIH HHS/United States; JID: 101233170; NIHMS941367; 2016/12/07 00:00 [received]; 2017/05/02 00:00 [revised]; 2017/10/13 00:00 [accepted]; 2017/11/14 06:00 [pubmed]; 2017/11/14 06:00 [medline]; 2017/11/14 06:00 [entrez]; ppublish |