AZD1775 and anti-PD-1 antibody synergistically sensitize hepatoma to radiotherapy.
10.1097/CM9.0000000000002988
- Author:
Yichun YIN
1
;
Jian WANG
2
;
Junxuan YI
1
;
Kaiyue ZHANG
1
;
Zimeng YIN
1
;
Shunzi JIN
1
;
Baisong ZHENG
2
Author Information
1. Public Health of College, Jilin University, Jilin, Changchun 130021, China.
2. Institute of Virology and AIDS Research, The First Hospital of Jilin University, Jilin, Changchun 130021, China.
- Publication Type:Journal Article
- MeSH:
Humans;
Animals;
Mice;
Carcinoma, Hepatocellular/radiotherapy*;
Cell Cycle Proteins/metabolism*;
Protein-Tyrosine Kinases/genetics*;
Apoptosis;
Programmed Cell Death 1 Receptor;
Cell Line, Tumor;
G2 Phase Cell Cycle Checkpoints;
Liver Neoplasms/radiotherapy*;
Tumor Microenvironment;
Pyrazoles;
Pyrimidinones
- From:
Chinese Medical Journal
2024;137(2):222-231
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:Radiation (IR)-induced DNA damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment (TME). Wee1, a cell cycle regulator, can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1 (CDK1). Meanwhile, programed death-1/programed death ligand-1 (PD-1/PDL-1) blockade is closely related to TME. This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody (anti-PD-1 Ab) on radiosensitization of hepatoma.
METHODS:The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide (MTT) assay on human and mouse hepatoma cells HepG2, Hepa1-6, and H22. The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro . A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice, which were divided into control group, IR group, AZD1775 group, IR + AZD1775 group, IR + anti-PD-1 Ab group, and the IR + AZD1775 + anti-PD-1 Ab group. Cytotoxic CD8 + T cells in TME were analyzed by flow cytometry.
RESULTS:Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro . AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced DNA damage. AZD1775 treatment also reduced the proportion of PD-1 + /CD8 + T cells in the spleen of hepatoma subcutaneous xenograft mice. Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferon γ (IFNγ) + or Ki67 + CD8 T cells and decreasing the levels of CD8 + Tregs cells in the tumor and spleen of the hepatoma mice model, indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγ expression, enhancing CD8 + T cells proliferation, and weakening CD8 + T cells depletion.
CONCLUSIONS:This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced DNA damage and improving cytotoxic CD8 + T cells in TME.
