一种由瘤性病毒释放的TGFβ抑制剂克服了免疫抑制性瘤微环境
Kristin DePeaux1, Dayana B Rivadeneira1, Konstantinos Lontos2
1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
The Journal of experimental medicine
|August 8, 2023
概括
检查点阻塞免疫疗法耐药性可以通过瘤性病毒 (VV) 克服. 提供TGFβ抑制剂的工程VV抑制了免疫抑制,增强了抗癌免疫力,并与检查点封锁协同作用.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 病毒学 病毒学
背景情况:
- 检查点阻塞免疫疗法受限于需要先前存在的免疫透物.
- 对抗α-PD-1的头状细胞癌 (HNSCC) 模型对于研究治疗耐药性至关重要.
- 瘤病毒 (VV) 可以诱导免疫透,但抵抗机制需要进一步研究.
研究的目的:
- 为了研究αPD-1敏感和耐药HNSCC瘤之间的免疫学差异.
- 探索型疫苗病毒 (VV) 在克服免疫疗法耐药性的潜力.
- 开发一种新的治疗策略,使用VV来提供免疫抑制抑制剂.
主要方法:
- 产生抗αPD-1和抗VV的小鼠HNSCC (MEER) 模型.
- 免疫透和细胞因子 (例如,TGFβ,IFNγ) 的分析,以应对免疫疗法.
- 工程VV表达转变生长因子β受体II (TGFβRII) 抑制剂.
- 在耐药瘤模型中对工程 VV 疗效的评估以及与检查点封锁相结合.
主要成果:
- 虽然敏感和耐药的瘤在VV治疗后都显示出免疫透和IFNγ产生,但耐药性与免疫抑制TGFβ的升高有关.
- TGFβ信号使IFNγ活性减弱,特别是在调节性T细胞中,导致治疗耐药性.
- 在耐药模型中,表达TGFβRII抑制剂的工程VV诱导了瘤回归.
- 工程 VV 和检查点封锁的组合疗法显示出显著的协同作用.
- 瘤特异性TGFβ抑制的病毒传递避免了全身毒性.
结论:
- 瘤病毒可以刺激免疫透,并将免疫抑制抑制剂直接传递给瘤.
- 通过VV提供TGFβ抑制的向输送提供了一个有前途的策略,以克服HNSCC的免疫疗法耐药性.
- 这种方法增强了抗瘤免疫力,并显示了与检查点封锁结合治疗的潜力,而无系统毒性.
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