CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response.
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, 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, X-Z; Mehrotra, S
Volume / Issue
Start / End Page
Pubmed Central ID
Electronic International Standard Serial Number (EISSN)
Digital Object Identifier (DOI)