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

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CD38-NAD+Axis Regulates Immunotherapeutic Anti-Tumor T Cell Response.
Cell Metabolism ( IF 27.7 ) Pub Date : 2018-Jan-09 , DOI: 10.1016/j.cmet.2017.10.006
Shilpak Chatterjee ₁ , Anusara Daenthanasanmak ₂ , Paramita Chakraborty ₁ , Megan W Wyatt ₂ , Payal Dhar ₂ , Shanmugam Panneer Selvam ₃ , Jianing Fu ₂ , Jinyu Zhang ₂ , Hung Nguyen ₂ , Inhong Kang ₄ , Kyle Toth ₁ , Mazen Al-Homrani ₁ , Mahvash Husain ₁ , Gyda Beeson ₅ , Lauren Ball ₅ , Kristi Helke ₄ , Shahid Husain ₆ , Elizabeth Garrett-Mayer ₇ , Gary Hardiman ₈ , Meenal Mehrotra ₄ , Michael I Nishimura ₉ , Craig C Beeson ₅ , Melanie Gubbels Bupp ₁₀ , Jennifer Wu ₂ , Besim Ogretmen ₃ , Chrystal M Paulos ₂ , Jeffery Rathmell ₁₁ , Xue-Zhong Yu ₂ , Shikhar Mehrotra ₁

Affiliation

Department of Surgery, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Biochemistry and Molecular Biology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Pathology and Laboratory Medicine, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Pharmaceutical and Biomedical Sciences, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Ophthalmology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Public Health, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Nephrology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC 29425, USA.
Department of Surgery, Loyola University, Maywood, IL 60153, USA.
Randolph-Macon College, Ashland, VA 23005, USA.
Department of Pathology, Microbiology, and Immunology, Vanderbilt University, Nashville, TN 37232, USA.

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.

中文翻译：

CD38-NAD +轴调节免疫治疗抗肿瘤T细胞反应。

增强的效应子功能和持久的持久性分别是Th1和Th17细胞的关键属性，是有效的抗肿瘤T细胞的关键特征。在这里，我们建立了离体培养条件，以产生杂合的Th1 / 17细胞，该细胞在体内长期维持，同时保持其效应子功能。使用转录组学和代谢谱分析方法，我们表明Th1 / 17细胞增强的抗肿瘤特性取决于组蛋白脱乙酰基酶Sirt1的NAD ⁺依赖性活性的增加。Sirt1活性的药理或遗传抑制削弱了Th1 / 17细胞的抗肿瘤潜力。重要的是，NADase CD38表面表达降低的T细胞固有地具有更高的NAD ⁺，增强的氧化磷酸化，更高的谷氨酰胺分解和改变的线粒体动力学，从而大大改善了肿瘤的控制。最后，即使使用Th0抗肿瘤T细胞，阻断CD38的表达仍可改善肿瘤控制。因此，针对CD38-NAD ⁺轴的策略可以提高抗肿瘤过继性T细胞疗法的疗效。

更新日期：2018-02-02

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