低剂量卡博普拉丁修改了瘤微环境,以增加人类前列腺癌模型中CAR T细胞的疗效
L H Porter1, J J Zhu2,3, N L Lister1
1Prostate Cancer Research Group, Monash Biomedicine Discovery Institute, Cancer Program, Department of Anatomy and Developmental Biology, Monash University, Clayton, VIC, 3800, Australia.
Nature communications
|September 2, 2023
概括
化疗与carboplatin增强了T细胞治疗前列腺癌的化学抗原受体 (CAR),通过改善T细胞透到瘤微环境 (TME). 这种组合疗法显示出对固体瘤治疗的前景.
科学领域:
- 在瘤学瘤学.
- 免疫治疗是一种免疫疗法.
- 癌症生物学 癌症生物学
背景情况:
- 化学抗原受体 (CAR) T细胞对血液癌症有效,但由于免疫抑制性瘤微环境 (TME),与固体瘤作斗争.
- 前列腺癌仍然是一个重大挑战,需要新的治疗策略.
- 易斯Y (Le Y) 抗原是某些癌症中CAR T细胞治疗的标.
研究的目的:
- 在前列腺癌患者衍生异种移植 (PDX) 模型中评估Le Y特异性CAR T细胞的疗效.
- 调查卡博普拉丁对CAR T细胞透和TME内的疗效的影响.
- 了解卡博普拉丁可以增强CAR T细胞治疗的机制.
主要方法:
- 在体外评估Le Y CAR T细胞对前列腺癌有机体的活性.
- 在实体研究中,使用前列腺癌PDX模型治疗Le Y CAR T细胞,单独或与卡博普拉丁结合.
- 分析TME变化,包括免疫细胞透,纤维细胞表型,细胞外矩阵和巨分化,在卡博普拉丁治疗后.
主要成果:
- Le Y CAR T细胞在体外表现出对前列腺癌有机体的细胞毒性.
- 单独使用碳白治疗并没有减少瘤生长,但显著增强了CAR T细胞透,并减少了瘤负担 in vivo.
- 卡博普拉丁诱导了促炎性TME,改变了与癌症相关的纤维细胞,降解了细胞外基质,并促进了M1巨细胞的分化,这促进了CAR T细胞透.
- 即使在不太敏感于碳烯的PDX模型中,CAR T细胞透也得到了改善,从而减少了瘤负担并增加了T细胞激活.
结论:
- 甲的预治疗可以克服TME介导的耐药性,并提高Le Y特异性CAR T细胞治疗前列腺癌的疗效.
- 卡博普拉丁对TME的促炎作用对于促进CAR T细胞透和抗瘤活性至关重要.
- 卡博普拉丁和CAR T细胞的组合代表了治疗固体瘤的有希望的策略,其反应受到TME调制的影响.
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