美国威尔康奈尔医学院Vivek Mittal小组发现,代谢调节因子PKM2的缺乏可激活五碳糖磷酸途径,并生成TCF1+前体CD8+ T细胞,从而改善免疫治疗。这一研究成果于2024年9月26日在线发表在国际学术期刊《自然—免疫学》上。
研究人员显示,通过删除丙酮酸激酶肌肉型2(PKM2)来靶向糖酵解会导致五碳糖磷酸途径(PPP)活性升高,从而富集TCF1高表达的前体耗竭样表型,并增加体内对PD-1阻断的反应性。PKM2KO CD8+ T细胞显示出降低的糖酵解通量、糖酵解中间产物和PPP代谢物的积累,以及通过1,2-13C葡萄糖碳追踪确定的PPP循环增加。小分子激动剂在不急性抑制糖酵解的情况下偏向CD8+ T细胞向TCF1高表达群体转变,生成独特的转录组特征。采用激动剂处理的CD8+ T细胞的转移在结合PD-1阻断时增强了小鼠的肿瘤控制,并促进了患者来源肿瘤类器官的肿瘤杀伤。
该研究展示了一种新的代谢重编程,有助于促进免疫治疗效果的前体样T细胞状态。
据悉,TCF1高表达的前体CD8+ T细胞介导了免疫治疗的有效性,但其生成和维持机制尚不清楚。
附:英文原文
Title: Deficiency of metabolic regulator PKM2 activates the pentose phosphate pathway and generates TCF1+ progenitor CD8+ T cells to improve immunotherapy
Author: Markowitz, Geoffrey J., Ban, Yi, Tavarez, Diamile A., Yoffe, Liron, Podaza, Enrique, He, Yongfeng, Martin, Mitchell T., Crowley, Michael J. P., Sandoval, Tito A., Gao, Dingcheng, Martin, M. Laura, Elemento, Olivier, Cubillos-Ruiz, Juan R., McGraw, Timothy E., Altorki, Nasser K., Mittal, Vivek
Issue&Volume: 2024-09-26
Abstract: TCF1high progenitor CD8+ T cells mediate the efficacy of immunotherapy; however, the mechanisms that govern their generation and maintenance are poorly understood. Here, we show that targeting glycolysis through deletion of pyruvate kinase muscle 2 (PKM2) results in elevated pentose phosphate pathway (PPP) activity, leading to enrichment of a TCF1high progenitor-exhausted-like phenotype and increased responsiveness to PD-1 blockade in vivo. PKM2KO CD8+ T cells showed reduced glycolytic flux, accumulation of glycolytic intermediates and PPP metabolites and increased PPP cycling as determined by 1,2-13C glucose carbon tracing. Small molecule agonism of the PPP without acute glycolytic impairment skewed CD8+ T cells toward a TCF1high population, generated a unique transcriptional landscape and adoptive transfer of agonist-treated CD8+ T cells enhanced tumor control in mice in combination with PD-1 blockade and promoted tumor killing in patient-derived tumor organoids. Our study demonstrates a new metabolic reprogramming that contributes to a progenitor-like T cell state promoting immunotherapy efficacy.
DOI: 10.1038/s41590-024-01963-1
Source: https://www.nature.com/articles/s41590-024-01963-1
Nature Immunology:《自然—免疫学》,创刊于2000年。隶属于施普林格·自然出版集团,最新IF:31.25
官方网址:https://www.nature.com/ni/
投稿链接:https://mts-ni.nature.com/cgi-bin/main.plex
本期文章:《自然—免疫学》:Online/在线发表