一种CXCR4部分激动剂通过向多态核核髓衍生的抑制细胞和癌症驱动的颗粒形成来改善免疫疗法
bioRxiv : the preprint server for biology
|October 17, 2024
概括
用TFF2-MSA来向多态核核髓衍生的抑制细胞 (PMN-MDSCs) 增强了免疫疗法. 这种方法通过减少免疫抑制的PMN-MDSCs和增强抗瘤T细胞反应来恢复胃癌中的抗PD-1敏感性.
科学领域:
- 免疫学 免疫学 免疫学
- 在瘤学瘤学.
- 药理学 药理学是指药理学的学科.
背景情况:
- 多态核核髓衍生的抑制细胞 (PMN-MDSCs) 损害免疫疗法反应.
- CXCR4是血液形成的关键调节剂,也是PMN-MDSCs的潜在目标.
研究的目的:
- 为了研究TFF2-MSA的治疗潜力,CXCR4部分激动剂,与抗PD-1结合用于胃癌治疗.
- 阐明TFF2-MSA影响PMN-MDSC和抗瘤免疫的机制.
主要方法:
- TFF2 (CXCR4部分激动剂) 与小鼠血清白蛋白 (MSA) 的融合.
- 在胃癌小鼠模型中使用TFF2-MSA和抗PD-1的体内研究.
- 使用histidine脱碳酶 (Hdc) -GFP转基因小鼠追踪PMN-MDSCs.
- 在瘤组织和循环中分析PMN-MDSC子集和T细胞反应.
- 胃癌患者的PMN-MDSCs,TFF2和CD8+ T细胞的相关性分析.
主要成果:
- 在胃癌模型中,TFF2-MSA与抗PD-1协同作用,诱导瘤回归,抑制转移,并延长存活时间.
- TFF2-MSA选择性地降低了免疫抑制性CXCR4+PMN-MDSCs,同时保留了促炎性中性粒细胞.
- 该疗法促进了CD8+ T细胞介导的抗瘤反应,并减少了全身PMN-MDSC和颗粒形成.
- CXCR4对抗剂加上抗PD-1并没有产生类似的治疗益处.
- 在GC患者中扩大PMN-MDSCs (CXCR4+LOX-1+) 与TFF2水平和CD8+T细胞相反相关.
结论:
- 通过向PMN-MDSCs和颗粒形成,TFF2-MSA代表了一种恢复胃癌中抗PD-1敏感性的新策略.
- 部分CXCR4激动症为增强癌症免疫疗法提供了一个有前途的治疗途径.
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