Microbial metabolite-guided CAR T cell engineering enhances anti-tumor immunity via epigenetic-metabolic crosstalk

Sarah Staudt, Fabian Nikolka, Markus Perl, Julia Franz, Noemie Leblay, Xiaoli-Kat Yuan, Linda Warmuth, Matthias A Fantes, Aiste Skorpskaite, Teng Fei, Maria Bromberg, Patxi San Martin-Uriz, Juan Roberto Rodriguez-Madoz, Kai Ziegler-Martin, Nazdar Adil-Gholam, Pascal Benz, Phuc Tran Huu, Christoph Stein-Thoeringer, Michael Schmitt, Karin Kleigrewe, Fabian Freitag, Zeno Riester, Justus Weber, Kira Mangold, Hermann Einsele, Felipe Prosper, Wilfried Ellmeier, Dirk Busch, Alexander Visekruna, John Slingerland, Roni Shouval, Karsten Hiller, Marcel van den Brink, Patrick Pausch, Paola Neri, Michael Hudecek, Hendrik Poeck, Maik Luu
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Abstract

Emerging data have highlighted a correlation between microbiome composition and cancer immunotherapy outcome. While commensal bacteria and their metabolites are known to modulate the host environment, contradictory effects and a lack of mechanistic understanding impede the translation of microbiome-based therapies into the clinic. In this study, we demonstrate that abundance of the commensal metabolite pentanoate is predictive for survival of chimeric antigen receptor (CAR) T cell patients in two independent cohorts. Its implementation in the CAR T cell manufacturing workflow overcomes solid tumor microenvironments in immunocompetent cancer models by hijacking the epigenetic-metabolic crosstalk, reducing exhaustion and promoting naive-like differentiation. While synergy of clinically relevant drugs mimicked the phenotype of pentanoate-engineered CAR T cells in vitro, in vivo challenge showed inferior tumor control. Metabolic tracing of 13C-pentanoate revealed citrate generation in the TCA cycle via the acetyl- and succinyl-CoA entry points as a unique feature of the C5 aliphatic chain. Inhibition of the ATP-citrate lyase, which links metabolic output and histone acetylation, led to accumulation of pentanoate-derived citrate from the succinyl-CoA route and decreased functionality of SCFA-engineered CAR T cells. Our data demonstrate that microbial metabolites are incorporated as epigenetic imprints and implementation into CAR T cell production might serve as embodiment of the microbiome-host axis benefits for clinical applications.
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微生物代谢物引导的 CAR T 细胞工程通过表观遗传-代谢串联增强抗肿瘤免疫力
新出现的数据强调了微生物组组成与癌症免疫疗法结果之间的相关性。众所周知,共生细菌及其代谢产物可调节宿主环境,但相互矛盾的影响和缺乏对机理的了解阻碍了将基于微生物的疗法应用于临床。在这项研究中,我们证明了共生代谢产物戊酸盐的丰度可预测两个独立队列中嵌合抗原受体(CAR)T细胞患者的存活率。在 CAR T 细胞制造工作流程中使用这种物质,可以通过劫持表观遗传学-代谢串扰、减少衰竭和促进天真样分化来克服免疫功能正常癌症模型中的实体肿瘤微环境。虽然临床相关药物的协同作用在体外模拟了戊酸盐工程 CAR T 细胞的表型,但体内挑战显示肿瘤控制能力较差。对13C-戊酸盐的代谢追踪显示,在TCA循环中通过乙酰和琥珀酰-CoA入口点生成柠檬酸盐是C5脂肪链的一个独特特征。ATP 柠檬酸裂解酶将代谢输出和组蛋白乙酰化联系在一起,抑制该酶会导致从琥珀酰-CoA途径获得的戊酸柠檬酸积累,并降低 SCFA 工程 CAR T 细胞的功能。我们的数据表明,微生物代谢产物被纳入表观遗传学印记,将其应用于 CAR T 细胞的生产可体现微生物组-宿主轴对临床应用的益处。
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