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将类似收费的受体agonists与免疫检查点封锁相结合,会影响抗瘤疫苗的疗效

Donghwan Jeon¹, Ethan Hill², Jena E Moseman¹

¹Cancer Biology, University of Wisconsin-Madison, Madison, Wisconsin, USA.

Journal for immunotherapy of cancer

|May 3, 2024

概括

将类似收费受体 (TLR) 激动剂与某些免疫检查点抑制剂 (如抗CTLA-4) 结合起来,可以提高癌症疫苗的疗效. 然而,将TLR激动剂与抗PD-1结合在一起,由于调节性T细胞激活,有效性被废除.

科学领域:

免疫学免疫学免疫学
癌症研究癌症研究
疫苗学疫苗学疫苗学

背景情况:

T细胞检查点受体调节T细胞功能和抗瘤功效.
收费类受体 (TLR) 激动剂可以调节T细胞激活和PD-1表达.
之前的研究结果显示,TLR激动因子减弱了因同源抗原激活的T细胞上的PD-1表达.

研究的目的:

调查是否结合TLR激动剂与免疫检查点阻塞可以增强疫苗介导的T细胞抗瘤免疫力.
在小鼠瘤模型中评估结合TLR激动剂和各种免疫检查点抑制剂的疗效.

主要方法:

结合TLR3和TLR9抗体 (TLR3加TLR9) 和免疫检查点抑制剂 (抗PD-1,抗CTLA-4,抗LAG-3,抗TIM-3,抗VISTA) 与疫苗或疫苗激活的CD8+ T细胞进行了组合.
治疗对EG7-OVA或MyC-CaP瘤携带的小鼠进行.
评估了瘤的生长,并通过流式细胞计量分析了瘤.

主要成果:

与单个治疗相比,SIINFEKL类疫苗,TLR激动剂和抗CTLA-4的组合显示出更高的抗瘤疗效.
结合疫苗和TLR激动剂与抗PD-1废除的抗瘤疗效,与TLR激动剂诱导的PD-1抑制和调控性T细胞 (Treg) 激活相关.
耗Tregs增强了组合治疗的疗效,即使与抗PD-1一起,这表明Tregs调解了废除.
与抗CTLA-4或抗LAG-3的组合显示出比抗TIM-3或抗VISTA的组合更大的抗瘤效果.

结论:

将TLR激动剂与抗CTLA-4或抗LAG-3结合起来,可以显著提高癌症疫苗的疗效.
使用抗PD-1与TLR激动剂结合使用是无效的,因为Treg激活.
对TLR激动剂和免疫检查点封锁的最佳组合对增强人类抗癌疫苗具有前途.

关键词:

免疫检查点抑制剂免疫检查点抑制剂前列腺癌是前列腺癌.一个T调节单元 - - Treg调节单元收费类受体 - - TLR 疫苗疫苗疫苗疫苗

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