PO.MCB09.04 · 分子与细胞生物学
新生儿CD8+ T细胞中丙酮酸代谢的重塑改变功能性和抗肿瘤免疫
Rewiring of pyruvate metabolism in neonatal CD8 + T cells alters functionality and antitumor immunity
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
神经母细胞瘤（NBL）是儿童中最常见的颅外实体瘤，约占儿童癌症相关死亡的15%。尽管高危疾病的结局相对较差，但18个月以下的儿童常表现出肿瘤的自发消退。导致NBL自发消退的机制尚未完全阐明，可能同时包含细胞内在和外在特征。与高危NBL相对较差的免疫原性形成对比，消退的肿瘤具有独特的免疫学特征，提示免疫系统可能在此过程中发挥关键作用。随着免疫系统的发育，单个免疫细胞的功能在生命早期是动态的。我们推测，婴儿免疫系统的功能差异可能为针对NBL的抗肿瘤免疫提供固有优势。特别是，与成人对应物相比，新生儿CD8+ T细胞具有增强的增殖潜能、增强的细胞因子产生，并可能抵抗耗竭。我们假设新生儿T细胞增强的功能性受不同的细胞代谢通路利用所控制。我们发现，在体外激活后，与成人T细胞相比，新生儿CD8+ T细胞具有与细胞代谢相关基因的独特RNA表达谱。与中心碳代谢相关的通路表达在新生儿和成人T细胞之间存在显著差异。丙酮酸作为这些过程的中心代谢枢纽，同位素异构体示踪揭示新生儿T细胞处理丙酮酸的方式与成人细胞不同。细胞外丙酮酸补充对新生儿CD8+ T细胞的增殖和效应细胞因子产生是必需的。新生儿T细胞优先将丙酮酸转化为丙氨酸，表明谷氨酸丙酮酸转氨酶（GPT）反应的使用增强。正在进行的研究将确定这一新发现的新生儿T细胞代谢特征的亚细胞区室化（即胞质、线粒体）以及肿瘤微环境中NBL施加的代谢限制对其的影响。
查看英文原文 English abstract
Neuroblastoma (NBL) is the most common extracranial solid tumor in children, accounting for ~15% of pediatric cancer-related deaths. Despite these relatively poor outcomes in high-risk disease, children under 18 months of age often demonstrate spontaneous tumor regression. The mechanisms leading to spontaneous NBL regression are incompletely described and likely consist of both cell intrinsic and extrinsic features. In contrast to the relatively poor immunogenicity of high-risk NBL, regressing tumors have a distinct immunological “signature” suggesting the immune system may play a critical role in this process. The function of individual immune cells is dynamic in early life as the immune system develops. We posited that functional differences in the infant immune system could provide inherent advantages for antitumor immunity against NBL. In particular, neonatal CD8 + T cells have increased proliferative potential, enhanced cytokine production, and may resist exhaustion relative to their adult counterparts. We hypothesized the enhanced functionality of neonatal T cells is controlled by the utilization of distinct pathways of cellular metabolism. We identified that following in vitro activation, neonatal CD8 + T cells have distinct RNA expression profiles of genes related to cell metabolism compared to adult T cells. The expression of pathways associated with central carbon metabolism were markedly different between neonatal and adult T cells. Pyruvate serves as the central metabolite hub for these processes, and isotopomer tracing revealed that neonatal T cells process pyruvate differently than adult cells. Extracellular pyruvate supplementation was essential for the proliferation and effector cytokine production in neonatal CD8 + T cells. Neonatal T cells had a preferential conversion of pyruvate to alanine indicating an enhanced use of the glutamic pyruvate transaminase (GPT) reaction. Ongoing studies will identify the subcellular compartmentalization (i.e. cytoplasmic, mitochondrial) and impact of NBL-imposed metabolic constraints in the tumor microenvironment on this newly identified metabolic feature of neonatal T cells.
利益披露 Disclosure
E. DeCleene, None..
A. Reynolds, None..
D. Vega-Mendoza, None..
R. Rodriguez, None..
M. Achom, None..
N. Lidman, None..
J. Almeida-Santos, None..
G. Rish, None..
S. Markson, None..
J. H. Rowe, None.