免疫检查点阻断通过扩增效应 CD8⁺ T 细胞克隆增强淋巴细胞清除性化疗诱导的抗肿瘤免疫
Immune Checkpoint Blockade Augments Lymphodepleting Chemotherapy-Induced Antitumor Immunity by Expanding Effector CD8+ T-cell Clones.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
阿尔茨海默病相关淀粉样β前体蛋白通过防止衰老应激诱导的线粒体自噬和延胡索酸耗竭来改善抗肿瘤免疫
英文原题：Alzheimer's Disease-Associated Amyloid-β Precursor Protein Prevents Aging Stress-Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity.
查看英文原题
Alzheimer's Disease-Associated Amyloid-β Precursor Protein Prevents Aging Stress-Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity.
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中文摘要
无标签：阿尔茨海默病（AD）患者的癌症发病率降低，一项全国成人样本的横断面分析发现，非AD个体被诊断为癌症的几率是AD患者的21倍。在本研究中，我们证明，AD相关淀粉样β前体蛋白（APP）及其裂解产物淀粉样β 40的线粒体定位，而非缺乏线粒体定位信号的突变APP，可抑制衰老T细胞中脂质应激介导的过度活跃线粒体自噬，改善其抗肿瘤功能。在AD小鼠中，黑色素瘤异种移植或致癌物诱导的口腔癌模型的生长高度减少。此外，使用从AD小鼠分离的衰老T细胞进行过继细胞转移免疫治疗可抑制肿瘤生长。T细胞中应激依赖性线粒体自噬的代谢特征显示延胡索酸耗竭，这与Parkin琥珀酸化减少和线粒体损伤增强相关。在机制上，APP与线粒体外膜TOMM复合物的相互作用减弱了衰老AD T细胞中神经酰胺合成酶CerS6向线粒体的转运，阻止了神经酰胺依赖性线粒体自噬。因此，APP恢复了线粒体延胡索酸代谢和Parkin琥珀酸化，改善了AD T细胞在体外和体内的抗肿瘤功能。外源性延胡索酸补充或健康AD线粒体转移在功能上模拟了衰老T细胞中的AD/APP表型，增强其抗肿瘤活性以控制肿瘤生长。此外，从衰老供者分离的T细胞显示线粒体自噬升高伴延胡索酸耗竭，而从年龄匹配的AD患者分离的T细胞中该现象得到恢复。总之，这些发现表明，AD通过保护T细胞免受神经酰胺依赖性线粒体自噬和延胡索酸耗竭的影响，增强抗肿瘤功能。意义：阿尔茨海默病患者癌症风险降低是由淀粉样蛋白β40肽介导的，该肽抑制T细胞中衰老依赖性线粒体自噬，从而改善抗肿瘤免疫。参见Bieberich的相关评论，第3579页。
展开英文摘要原文
UNLABELLED: Patients with Alzheimer's disease (AD) have a decreased incidence of cancer, with a cross-sectional analysis of a nationwide sample of adults finding 21-fold higher odds of cancer diagnosis in non-AD individuals compared with those with AD.
In this study, we demonstrated that mitochondrial localization of AD-associated amyloid-β precursor protein (APP) and its cleavage product amyloid-β 40, but not mutant APP that lacks a mitochondrial localization signal, inhibits lipid stress-mediated hyperactive mitophagy in aging T cells, improving their antitumor functions. Growth of melanoma xenograft or carcinogen-induced oral cancer models was highly reduced in AD mice.
Additionally, adoptive cell transfer-based immunotherapy using aging T cells isolated from AD mice suppressed tumor growth. The metabolic signature of stress-dependent mitophagy in T cells showed fumarate depletion, which was linked to decreased succination of Parkin and enhanced mitochondrial damage.
Mechanistically, APP interaction with the TOMM complex at the outer mitochondrial membrane attenuated trafficking of ceramide synthase CerS6 to mitochondria in aging AD T cells, preventing ceramide-dependent mitophagy.
Thus, APP restored mitochondrial fumarate metabolism and Parkin succination, improving antitumor functions of AD T cells in vitro and in vivo. Exogenous fumarate supplementation or healthy AD mitochondria transfer functionally mimicked the AD/APP phenotype in aging T cells, enhancing their antitumor activity to control tumor growth.
Moreover, T cells isolated from aging donors showed elevated mitophagy with fumarate depletion, which was restored in T cells isolated from age-matched patients with AD.
Together, these findings show that AD protects T cells against ceramide-dependent mitophagy and fumarate depletion to enhance antitumor functions. SIGNIFICANCE: The reduced cancer risk in Alzheimer's disease patients is mediated by the amyloid-β 40 peptide, which inhibits aging-dependent mitophagy in T cells to improve antitumor immunity. See related commentary by Bieberich, p. 3579.
论文信息
- 作者
- Kassir MF、Lee HG、Oleinik NV、Wofford W、Walton C、Atilgan FC、Janneh AH、Chakraborty P
- 单位
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina.United States
- 文献类型
- 美国 NIH 资助研究
- 期刊
- Cancer research2025 Oct 1
- 原文标识
- PubMed 40773679 · DOI 10.1158/0008-5472.CAN-24-4740
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