Dataset Information

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.

SUBMITTER: Chatterjee S

PROVIDER: S-EPMC5837048 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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CD38-NAD<sup>+</sup>Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response.

Chatterjee Shilpak S Daenthanasanmak Anusara A Chakraborty Paramita P Wyatt Megan W MW Dhar Payal P Selvam Shanmugam Panneer SP Fu Jianing J Zhang Jinyu J Nguyen Hung H Kang Inhong I Toth Kyle K Al-Homrani Mazen M Husain Mahvash M Beeson Gyda G Ball Lauren L Helke Kristi K Husain Shahid S Garrett-Mayer Elizabeth E Hardiman Gary G Mehrotra Meenal M Nishimura Michael I MI Beeson Craig C CC Bupp Melanie Gubbels MG Wu Jennifer J Ogretmen Besim B Paulos Chrystal M CM Rathmell Jeffery J Yu Xue-Zhong XZ Mehrotra Shikhar S

Cell metabolism 20171109 1

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<sup>+</sup>-dependent acti ...[more]

PMID: 29129787

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Project description:BackgroundCancer cell metabolism requires sustained pools of intracellular nicotinamide adenine dinucleotide (NAD+) which is maintained by a balance of NAD+ hydrolase activity and NAD+ salvage activity. We recently reported that human prostate cancer can be initiated following oncogene expression in progenitor-like luminal cells marked by low expression of the NAD+-consuming enzyme CD38. CD38 expression is reduced in prostate cancer compared to benign prostate, suggesting that tumor cells may reduce CD38 expression in order to enhance pools of NAD+. However, little is known about how CD38 expression is repressed in advanced prostate cancer and whether CD38 plays a role in regulating NAD+ levels in prostate epithelial cells.MethodsCD38 expression, its association with recurrence after prostatectomy for clinically localized prostate cancer, and DNA methylation of the CD38 promoter were evaluated in human prostate tissues representing various stages of disease progression. CD38 was inducibly over-expressed in benign and malignant human prostate cell lines in order to determine the effects on cell proliferation and levels of NAD+ and NADH. NAD+ and NADH were also measured in urogenital tissues from wild-type and CD38 knockout mice.ResultsCD38 mRNA expression was reduced in metastatic castration-resistant prostate cancer compared to localized prostate cancer. In a large cohort of men undergoing radical prostatectomy, CD38 protein expression was inversely correlated with recurrence. We identified methylation of the CD38 promoter in primary and metastatic prostate cancer. Over-expression of wild-type CD38, but not an NAD+ hydrolase-deficient mutant, depleted extracellular NAD+ levels in benign and malignant prostate cell lines. However, expression of CD38 did not significantly alter intracellular NAD+ levels in human prostate cell lines grown in vitro and in urogenital tissues isolated from wild-type and CD38 knockout mice.ConclusionsCD38 protein expression in prostate cancer is associated with risk of recurrence. Methylation results suggest that CD38 is epigenetically regulated in localized and metastatic prostate cancer tissues. Our study provides support for CD38 as a regulator of extracellular, but not intracellular, NAD+ in epithelial cells. These findings suggest that repression of CD38 by methylation may serve to increase the availability of extracellular NAD+ in prostate cancer tissues.

Dataset Information

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

Publications

CD38-NAD<sup>+</sup>Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response.

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