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经CXCL9 / 10工程设计的树突细胞促进T细胞激活,增强肺癌免疫检查点阻塞

Raymond J Lim¹, Ramin Salehi-Rad², Linh M Tran²

¹Division of Pulmonary and Critical Care, Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, CA 90095, USA.

Cell reports. Medicine

|March 22, 2024

概括

用工程树突细胞 (CXCL9/10-DC) 进行内接种,可以增强T细胞对非小细胞肺癌的反应. 这种方法与免疫检查点封锁 (ICB) 相结合,克服了治疗耐药性并促进了全身免疫力.

科学领域:

免疫学免疫学免疫学
在瘤学瘤学.
癌症治疗癌症治疗

背景情况:

使用PD-1/PD-L1抑制剂的免疫检查点阻塞 (ICB) 已经改变了非小细胞肺癌 (NSCLC) 治疗,但只有少数患者获得持久反应.
对ICB的耐药性通常与抗原呈现不佳和免疫抑制性瘤微环境 (TME) 有关,这些微环境阻碍了T细胞的透和激活.
开发增强T细胞介导抗瘤免疫力的策略对于提高NSCLC中ICB疗效至关重要.

研究的目的:

评估用树突细胞进行内注射 (IT) 疫苗接种,以表达CXCL9和CXCL10 (CXCL9/10-DC),作为克服NSCLC中ICB耐药性的方法.
阐明IT CXCL9/10-DC增强抗瘤免疫反应的机制,包括T细胞在TME中的招募和激活.
在临床前NSCLC模型中评估IT CXCL9/10-DC和ICB的联合治疗,以克服耐药性并建立全身抗瘤免疫力.

主要方法:

使用非小细胞肺癌 (NSCLC) 的小鼠模型来测试用CXCL9/10工程 dendritic 细胞 (CXCL9/10-DC) 进行内接种 (IT) 疫苗的疗效.
评估瘤微环境 (TME) 和淋巴结中的T细胞透,激活和贩运 (包括CD4+,CD8+和CXCR3依赖机制).
评估了单独使用IT CXCL9/10-DC和结合免疫检查点阻塞 (ICB) 对瘤生长和全身免疫的治疗结果.

主要成果:

内CXCL9/10-DC疫苗接种显著增强了TME内的T细胞透和激活,导致小鼠NSCLC模型中的瘤抑制.
IT CXCL9/10-DC的抗瘤作用取决于CD4+和CD8+T细胞的存在,以及CXCR3介导的T细胞贩运.
在临床前模型中,IT CXCL9/10-DC与ICB的联合治疗有效地克服了ICB耐药性,并建立了持久的,瘤特异性的全身免疫力.

结论:

内CXCL9/10-DC疫苗接种是一种有希望的策略,可以增强T细胞介导的抗瘤免疫力,并在非小细胞肺癌中克服对免疫检查点阻塞的抵抗力.
该机制涉及通过CXCL9/10化学基因表达和CXCR3依赖性贩运增强的T细胞招募和激活.
这些发现为IT CXCL9/10-DC的临床转化提供了强有力的理由,以改善NSCLC患者的ICB疗效.

关键词:

在CXCL10中,CXCL10是CXCL10中的一个.在CXCL9中使用.在CXCR3中,CXCR3是最常见的.在NSCLCLC中,我们可以看到NSCLCLC.在T细胞,T细胞.检查站封锁检查站封锁树突细胞是一种树突细胞.免疫抑制是一种免疫抑制.在现场接种疫苗.系统免疫力系统免疫力

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