Everolimus (RAD001) combined with programmed death-1 (PD-1) blockade enhances radiosensitivity of cervical cancer and programmed death-ligand 1 (PD-L1) expression by blocking the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) pathway

Bioengineered

卷:13

Shikai Liu¹  Sufen Zhao²  Lili Song² 

[1] Department of Obstetrics and Gynecology, Cangzhou Central Hospital, Cangzhou, Hebei, China;

[2] Department of Obstetrics and Gynecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China;

关键词: Cervical cancer;    everolimus;    programmed cell death 1 receptor;    programmed cell death-ligand 1;    PI3K/AKT/mTOR pathway;    autophagy;   

DOI  :  10.1080/21655979.2022.2064205

来源: DOAJ

【 摘 要 】

Cervical cancer (CC) is the 4th most prevalent malignancy in females. This study explored the mechanism of everolimus (RAD001) combined with programmed death-1 (PD-1) blockade on radiosensitivity by phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and autophagy in CC cells. Low-radiosensitive CaSki cells were selected as study objects. After RAD001 treatment, PI3K/AKT/mTOR pathway activation, autophagy, migration and invasion abilities, autophagy-related proteins (LC3-I, LC3-II, and p62), and PD-L1 expression in CC cells were detected. After triple treatment of radiotherapy (RT), RAD001, and PD-1 blockade to the CC mouse models, tumor weight and volume were recorded. Ki67 expression, the number of CD8 + T cells, and the ability to produce IFN-γ and TNF-α in tumor tissues were determined. RAD001 promoted autophagy by repressing PI3K/AKT/mTOR pathway, augmented RT-induced apoptosis, and weakened migration and invasion, thereby increasing CC cell radiosensitivity. RAD001 elevated RT-induced PD-L1 level. RT combined with RAD001 and PD-1 blockade intensified the inhibitory effect of RT on tumor growth, reduced the amount of Ki67-positive cells, enhanced radiosensitivity of CC mice, and increased the quantity and killing ability of CD8 + T cells. Briefly, RAD001 combined with PD-1 blockade increases radiosensitivity of CC by impeding the PI3K/AKT/mTOR pathway and potentiating cell autophagy.

【 授权许可】

Unknown