CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response
Open accessAbstract
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.
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CD38 regulates immune-cell homing, innate immune responses to pathogens and antitumour immunity.
“Previous studies have reported that CD38 regulates immune-cell homing, innate immune responses to pathogens and antitumour immunity63-65.”
From Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages (2020) · cites this paper as [63]
Upregulation of the NAD+-SIRT1-FOXO1 axis via CD38 inhibition increases effector functions in T helper 1 and 17 hybrid cells.
“The upregulation of the NAD+–SIRT1–FOXO1 axis via CD38 inhibition increases effector functions in T helper 1 and 17 hybrid cells117”
From NAD+ metabolism and its roles in cellular processes during ageing (2021) · cites this paper as [117]
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References 60 · Cited by 270
- 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.
- Affiliations
- Medical University of South Carolina (US)
- Loyola University Chicago (US)
- Randolph–Macon College (US)
- Corresponding author
- Mehrotra, Shikhar
- ORCID
- Chatterjee, Shilpak
- Daenthanasanmak, Anusara
- Chakraborty, Paramita
- Dhar, Payal
- Selvam, Shanmugam Panneer
- Fu, Jianing
- Zhang, Jinyu
- Nguyen, Hung
- Ball, Lauren
- Helke, Kristi
- Husain, Shahid
- Garrett-Mayer, Elizabeth
- Hardiman, Gary
- Mehrotra, Meenal
- Nishimura, Michael I.
- Bupp, Melanie Gubbels
- Wu, Jennifer
- Paulos, Chrystal M.
- Yu, Xue-Zhong
- Mehrotra, Shikhar
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 27
- Issue
- 1
- Pages
- 85-100.e8
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5837048
- OpenAlex
- W2767761069
- Cited by
- 270
- References
- 60
- Citations by year
- 2026: 24 · 2025: 29 · 2024: 37 · 2023: 29 · 2022: 38 · 2021: 37 · 2020: 36 · 2019: 21 · 2018: 19
- FWCI
- 9.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 374 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01CA138930, R21CA137725, P01CA154778)
- DOD Prostate Cancer Research Program (W81XWH-16-1-0273)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- CD38, NAD+, SIRT1, antitumor T-cell responses, adoptive T cell therapy, NADase, oxidative phosphorylation, glutaminolysis, mitochondrial dynamics, T cell metabolism, cancer immunotherapy
- MeSH terms
- Forkhead Box Protein O1, Animals, Glutamine, Immunotherapy, Mice, Inbred C57BL, NAD, Neoplasms, T-Lymphocytes, Th1 Cells, ADP-ribosyl Cyclase 1, Sirtuin 1, Th17 Cells
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