<br>通过线粒体靶向阿托伐醌原位疫苗接种预防肿瘤生长和传播,Advanced Science

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通过线粒体靶向阿托伐醌原位疫苗接种预防肿瘤生长和传播
Advanced Science ( IF 14.3 ) Pub Date : 2022-03-04 , DOI: 10.1002/advs.202101267
Mofei Huang ₁ , Donghai Xiong ₁ , Jing Pan ₁ , Qi Zhang ₁ , Yian Wang ₁ , Charles R Myers ₂ , Bryon D Johnson ₃ , Micael Hardy ₄ , Balaraman Kalyanaraman ₅ , Ming You ₁

Affiliation

Atovaquone 是 FDA 批准的一种治疗疟疾的药物，已知可以抑制线粒体电子传递。最近合成的线粒体靶向阿托伐醌可增加线粒体积累和体外抗肿瘤活性。使用原位疫苗接种方法，将线粒体靶向的阿托伐醌局部注射到原发性肿瘤中，在局部和远处肿瘤部位引发有效的 T 细胞免疫反应。线粒体靶向阿托伐醌治疗导致肿瘤微环境中粒细胞骨髓源性抑制细胞和调节性 T 细胞显着减少。线粒体靶向阿托伐醌治疗可阻断粒细胞源性抑制细胞和调节性 T 细胞中参与氧化磷酸化和糖酵解的基因表达，这可能导致粒细胞源性抑制细胞和调节性 T 细胞死亡。靶向线粒体的阿托伐醌可抑制粒细胞骨髓源性抑制细胞和调节性 T 细胞中线粒体复合物成分、氧化磷酸化和糖酵解的基因表达。由此产生的肿瘤内粒细胞髓源性抑制细胞和调节性 T 细胞的减少可能会促进观察到的肿瘤浸润 CD4 ⁺ T 细胞的增加。线粒体靶向阿托伐醌还可提高 PD-1 阻断免疫疗法的抗肿瘤活性。结果表明，粒细胞骨髓来源的抑制细胞和调节性 T 细胞是线粒体靶向阿托伐醌的新靶标，可促进其抗肿瘤功效。

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Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria-Targeted Atovaquone

Atovaquone, an FDA-approved drug for malaria, is known to inhibit mitochondrial electron transport. A recently synthesized mitochondria-targeted atovaquone increased mitochondrial accumulation and antitumor activity in vitro. Using an in situ vaccination approach, local injection of mitochondria-targeted atovaquone into primary tumors triggered potent T cell immune responses locally and in distant tumor sites. Mitochondria-targeted atovaquone treatment led to significant reductions of both granulocytic myeloid-derived suppressor cells and regulatory T cells in the tumor microenvironment. Mitochondria-targeted atovaquone treatment blocks the expression of genes involved in oxidative phosphorylation and glycolysis in granulocytic-myeloid-derived suppressor cells and regulatory T cells, which may lead to death of granulocytic-myeloid-derived suppressor cells and regulatory T cells. Mitochondria-targeted atovaquone inhibits expression of genes for mitochondrial complex components, oxidative phosphorylation, and glycolysis in both granulocytic-myeloid-derived suppressor cells and regulatory T cells. The resulting decreases in intratumoral granulocytic-myeloid-derived suppressor cells and regulatory T cells could facilitate the observed increase in tumor-infiltrating CD4⁺ T cells. Mitochondria-targeted atovaquone also improves the anti-tumor activity of PD-1 blockade immunotherapy. The results implicate granulocytic-myeloid-derived suppressor cells and regulatory T cells as novel targets of mitochondria-targeted atovaquone that facilitate its antitumor efficacy.

更新日期：2022-03-04

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