Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell metabolism, 2018-01, Vol.27 (1), p.85-100.e8

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

ScienceDirect

Beschreibungen/Notizen

• 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. [Display omitted] •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 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.