癌症研究
肺癌
癌症
癌细胞
生物
微泡
效应器
T细胞
细胞
免疫学
医学
内科学
免疫系统
小RNA
生物化学
基因
作者
Ying Wang,Mengdi Liu,Lei Zhang,Xiyu Liu,Hanxu Ji,Yan Wang,Jian‐Fang Gui,Yongmin Yan,Zhenke Wen
标识
DOI:10.1038/s41419-023-06336-4
摘要
Abstract While ectonucleotidase CD39 is a cancer therapeutic target in clinical trials, its direct effect on T-cell differentiation in human non-small-cell lung cancer (NSCLC) remains unclear. Herein, we demonstrate that human NSCLC cells, including tumor cell lines and primary tumor cells from clinical patients, efficiently drive the metabolic adaption of human CD4 + T cells, instructing differentiation of regulatory T cells while inhibiting effector T cells. Of importance, NSCLC-induced T-cell mal-differentiation primarily depends on cancer CD39, as this can be fundamentally blocked by genetic depletion of CD39 in NSCLC. Mechanistically, NSCLC cells package CD39 into their exosomes and transfer such CD39-containing exosomes into interacting T cells, resulting in ATP insufficiency and AMPK hyperactivation. Such CD39-dependent NSCLC-T cell interaction holds well in patients-derived primary tumor cells and patient-derived organoids (PDOs). Accordingly, genetic depletion of CD39 alone or in combination with the anti-PD-1 immunotherapy efficiently rescues effector T cell differentiation, instigates anti-tumor T cell immunity, and inhibits tumor growth of PDOs. Together, targeting cancer CD39 can correct the mal-differentiation of CD4 + T cells in human NSCLC, providing in-depth insight into therapeutic CD39 inhibitors.
科研通智能强力驱动
Strongly Powered by AbleSci AI