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剂量特定的内转基因-CSF调节乳腺瘤氧化和抗瘤免疫力

Nicole E Mihalik^1,2, Kayla J Steinberger^1,2, Alyson M Stevens^1,2

¹Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, WV.

Journal of immunology (Baltimore, Md. : 1950)

|September 27, 2023

概括

低剂量颗粒细胞-巨细胞殖民地刺激因子 (GM-CSF) 降低瘤缺氧并使血管系统正常,使抗免疫治疗的癌症敏感. 高剂量的GM-CSF加剧了缺氧和免疫抑制,突出了有效治疗癌症的关键剂量考虑.

科学领域:

免疫学免疫学免疫学
在瘤学瘤学.
癌症生物学癌症生物学

背景情况:

颗粒细胞-巨细胞殖民地刺激因子 (GM-CSF) 是一种具有可变疗效的免疫疗法辅助剂.
之前的研究表明,高剂量的GM-CSF可以使三阴性乳腺癌 (TNBC) 的瘤缺氧和血管生成恶化.

研究的目的:

为了比较低剂量与高剂量GM-CSF的免疫调节和氧气调节效应.
在TNBC模型中评估GM-CSF对瘤氧化,血管和抗瘤免疫的影响.
为了确定GM-CSF的剂量是否会影响对抗PD1免疫疗法的敏感性.

主要方法:

在FVB/N PyMT TNBC模型中注射低剂量的GM-CSF或盐水.
评估瘤缺氧,血管 (CD31+内皮细胞,NG2+皮细胞) 和免疫细胞表型 (TAMs,TILs) 通过流细胞计和转录造型.
在GM-CSF原料PyMT (冷) 和BALB/c 4T1 (热) TNBC模型中对抗PD1反应的评估.

主要成果:

低剂量的GM-CSF减少了瘤缺氧,并通过增加细胞周覆盖率来正常化血管系统.
低剂量的GM-CSF使抗PD1耐药PyMT瘤对抗PD1疗法的敏感.
高剂量的GM-CSF加剧了缺氧,并在PyMT瘤中促进了免疫抑制的TAM表型.
高剂量的GM-CSF在4T1瘤中产生了不同的效果,增加了MHC类IIhiTAM和免疫刺激分子.

结论:

低剂量GM-CSF在减少瘤缺氧,增强血管正常化和改善免疫疗法反应方面发挥了新的作用.
高剂量的GM-CSF可以促进免疫抑制瘤微环境,特别是在低氧条件下.
转基因-CSF剂量是影响瘤氧化,免疫反应和癌症免疫疗法的治疗疗效的关键因素.

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