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通过诱导CD163+M2巨细胞极化和MMP9分泌,EBV促进TCR-T细胞治疗的耐药性

Yuanyuan Chen^1,2, Dijun Ouyang¹, Yan Wang¹

¹Department of Biotherapy, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.

Journal for immunotherapy of cancer

|June 17, 2024

概括

爱斯坦-巴尔病毒 (EBV) 驱动M2巨分化,导致矩阵金属蛋白9 (MMP9) 分泌,导致T细胞耗尽,并限制EBV阳性瘤中TCR-T细胞治疗的疗效. 将MMP9抑制剂与TCR-T细胞结合起来,可以增强T细胞功能,抑制瘤生长.

科学领域:

在瘤学瘤学.
免疫学免疫学免疫学
病毒学病毒学

背景情况:

爱斯坦-巴尔病毒 (EBV) 是一种致癌病毒,与各种固体瘤有关.
目前针对EBV相关瘤的T细胞受体 (TCR) -T细胞疗法由于瘤的免疫抑制微环境而面临限制.

研究的目的:

阐明EBV对瘤免疫抑制微环境的贡献机制.
确定克服T细胞抑制和增强EBV阳性固体瘤TCR-T细胞治疗的策略.

主要方法:

流细胞计被用来分析巨细胞表型和T细胞功能.
使用异种移植小鼠模型来评估M2巨细胞,TCR-T细胞和矩阵金属蛋白9 (MMP9) 抑制剂对瘤生长的影响.

主要成果:

阳性EBV瘤显示T细胞疲劳,尽管T细胞透率高.
EBV感染通过CCL5,CSF1和IL10诱导了CD163+M2巨分化,导致大规模的MMP9分泌.
由M2巨细胞分泌的MMP9被确定为T细胞耗尽和TCR-T细胞治疗耐药性的关键因素.
抑制MMP9改善了T细胞功能,并与TCR-T细胞结合,显著抑制了瘤异种移植的生长.

结论:

矩阵金属蛋白9 (MMP9) 抑制剂可以抵消EBV诱导的M2巨对T细胞功能的抑制作用.
结合TCR-T细胞治疗与MMP9抑制剂,为EBV阳性固体瘤提供了一个有前途的治疗策略.

关键词:

头部和部新生体.免疫逃生是免疫逃生的一种方式.免疫治疗是一种免疫疗法.巨细胞是一个巨细胞.瘤微环境瘤微环境

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