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Pharmacological effects on anaplerotic pathways alter the metabolic landscape in the tumor microenvironment, causing unpredictable, sustained anti-tumor immunity
International Immunology ( IF 4.4 ) Pub Date : 2021-09-07 , DOI: 10.1093/intimm/dxab067
Heiichiro Udono 1 , Mikako Nishida 1
Affiliation  

Abstract
To achieve sustained anti-tumor immunity, tumor-infiltrating effector CD8 T lymphocytes (CD8 TILs) must be able to produce cytokines, including IFNγ, and proliferate robustly within the local tumor tissue upon antigen recognition. IFNγ production by CD8 TILs depends on glycolysis, whereas their proliferation additionally requires oxidative phosphorylation (OxPhos). The level of OxPhos, and hence the oxygen consumption rate, depends on mitochondrial biogenesis and requires the loading of metabolic precursors into the tricarboxylic acid cycle to keep it functioning. This is referred to as anaplerosis. Recent advances in the field of immuno-metabolism have shown the impact of pharmacological agents on anaplerotic pathways, resulting in metabolic down-regulation in tumor cells; in contrast, the agents trigger sustained anti-tumor immunity by up-regulating both glycolysis and OxPhos in CD8 TILs. The opposing effects of pharmacological inhibition (and/or activation) on anaplerosis in tumor cells and CD8 TILs are unpredictable. Careful dissection of the underlying mechanism might confer important knowledge, helping us to step into a new era for cancer immunotherapy.


中文翻译:

对回补途径的药理作用改变了肿瘤微环境中的代谢景观,导致不可预测的持续抗肿瘤免疫

摘要
为了实现持续的抗肿瘤免疫,肿瘤浸润效应 CD8 T 淋巴细胞 (CD8 TIL) 必须能够产生细胞因子,包括 IFNγ,并在抗原识别后在局部肿瘤组织内强劲增殖。CD8 TIL 产生的 IFNγ 依赖于糖酵解,而它们的增殖还需要氧化磷酸化 (OxPhos)。OxPhos 的水平以及因此的耗氧率取决于线粒体的生物发生,并且需要将代谢前体加载到三羧酸循环中以保持其功能。这被称为回补。免疫代谢领域的最新进展表明药物对回补途径的影响,导致肿瘤细胞代谢下调;相比之下,这些药物通过上调 CD8 TIL 中的糖酵解和 OxPhos 来触发持续的抗肿瘤免疫。药理学抑制(和/或激活)对肿瘤细胞和 CD8 TIL 的回补的相反作用是不可预测的。仔细剖析潜在机制可能会提供重要知识,帮助我们进入癌症免疫治疗的新时代。
更新日期:2021-09-07
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