一个有针对性的发育计划共同调节血管生成和免疫逃避
bioRxiv : the preprint server for biology
|January 7, 2025
概括
转录因子HOXD13通过增强血管形成和抑制抗瘤T细胞来促进黑色素瘤的生长. 抑制它的点,VEGF和腺受体,在模型中逆转了这种效应.
科学领域:
- 分子生物学分子生物学
- 癌症研究 癌症研究
- 免疫学 免疫学 免疫学
背景情况:
- 紫外线辐射诱导的DNA突变驱动黑色素瘤的启动和新抗原的形成,触发抗瘤免疫力.
- 黑色素瘤细胞通过调节表观遗传学和瘤微环境相互作用,包括血管生成来逃避免疫检测.
- 瘤增强血液流动,同时防止免疫细胞透,这是一个复杂的过程,涉及免疫逃避策略.
研究的目的:
- 研究转录因子 (TFs) 在黑色素瘤发育和免疫逃避中的作用.
- 在黑色素瘤中识别与血管生成和免疫细胞排除相关的特定TFs.
- 阐明HOXD13影响瘤生长,血管生成和免疫抑制的分子机制.
主要方法:
- 在早期黑色素瘤,纳维和其他癌症中对TF表达的比较分析.
- 转录学,3D染色体分析,以及体内黑色素瘤模型.
- 评估HOXD13对血管生成,T细胞透和基因调节的影响.
主要成果:
- 在黑色素瘤中,HOXD13的上调驱动着类似于黑色素细胞的程序,与血管生成的增加和抑制的T细胞透有关.
- 通过编排3D染色质接触,HOXD13激活VEGFA,SEMA3A和CD73,促进瘤生长.
- 维格法和SEMA3A重塑血管系统;CD73提高腺,一个血管扩张和免疫抑制剂.
结论:
- 在黑色素瘤中,HOXD13建立了一个双重的亲血管和免疫抑制轴 (HOXD13-CD73/VEGF).
- 在体内,HOXD13诱导的瘤生长被VEGFR和腺素受体 (AdR) 的联合抑制逆转.
- 确定潜在受益于联合AdR和VEGFR抑制剂治疗的患者子组.
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