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分泌CV1的嵌合抗原受体T细胞增强了微波消融在异质性肿瘤中的远隔效应。

CV1-secreting sCAR-T cells potentiate the abscopal effect of microwave ablation in heterogeneous tumors.

作者信息

Cao Bihui, Liu Manting, Xiao Zecong, Leng Dongliang, Zhou Yubo, Zhang Zhenfeng, Wang Lu, Huang Xinkun, Ni Qianqian, Cheng Wei, Assaraf Yehuda G, Zhao Qi, Shen Jia, Zhu Kangshun

机构信息

Department of Minimally Invasive Interventional Radiology, Department of Radiology, Central Laboratory, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China; Medical Sciences Program, Indiana University School of Medicine, Bloomington, IN 47405, USA.

Department of Minimally Invasive Interventional Radiology, Department of Radiology, Central Laboratory, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510260, China.

出版信息

Cell Rep Med. 2025 Feb 18;6(2):101965. doi: 10.1016/j.xcrm.2025.101965.

Abstract

Microwave ablation (MWA) triggers a weak systemic immune response that leads to the abscopal regression of distant metastases while killing local tumors, known as the abscopal effect. Combining MWA with chimeric antigen receptor (CAR)-T cells demonstrates promise in enhancing the abscopal effect in antigen-homogeneous tumors. However, the loss of the antigen recognized by CAR or intrinsic antigenic heterogeneity in solid tumors poses a major obstacle. SIRPα variant (CV1)-secreting CAR-T (sCAR-T) cells elicit an abscopal effect on distant tumors with antigen heterogeneity in mice receiving local MWA. Mechanistically, sCAR-T cells can locally eliminate antigen-positive tumors and secrete CV1, whereas the secreted CV1 can activate macrophages that migrate to non-ablated tumor sites in response to post-MWA chemokines, eliciting a macrophage-dependent abscopal effect that enables phagocytosis of antigen-heterogeneous cancer cells. This macrophage-dependent abscopal effect instigated by MWA and sCAR-T cells offers a clinically translatable strategy in metastatic solid tumors with antigen heterogeneity.

摘要

微波消融(MWA)在杀死局部肿瘤的同时引发微弱的全身免疫反应,导致远处转移灶发生远隔效应消退,即所谓的远隔效应。将MWA与嵌合抗原受体(CAR)-T细胞联合应用,有望增强抗原同质肿瘤的远隔效应。然而,CAR识别的抗原丢失或实体瘤中固有的抗原异质性构成了主要障碍。分泌信号调节蛋白α变体(CV1)的CAR-T(sCAR-T)细胞在接受局部MWA的小鼠中,对具有抗原异质性的远处肿瘤产生远隔效应。从机制上讲,sCAR-T细胞可以在局部清除抗原阳性肿瘤并分泌CV1,而分泌的CV1可以激活巨噬细胞,这些巨噬细胞会响应MWA后的趋化因子迁移到未消融的肿瘤部位,引发依赖巨噬细胞的远隔效应,使抗原异质性癌细胞被吞噬。这种由MWA和sCAR-T细胞引发的依赖巨噬细胞的远隔效应为具有抗原异质性的转移性实体瘤提供了一种可临床转化的策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3908/11866491/c6e358e6f5de/fx1.jpg

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