Enhancing Therapeutic Response and Overcoming Resistance to Checkpoint Inhibitors in Ovarian Cancer through Cell Cycle Regulation

Abstract

Tumor cells invade normal surrounding tissues through continuous division. In this study, we hypothesized that cell cycle regulation changes the immune efficacy of ovarian cancer. To investigate this hypothesis, a Förster resonance energy transfer (FRET) sensor was constructed to characterize the cell activity in real time. Cell shrinkage caused by apoptosis induces the aggregation of proteins on the cell membrane, leading to variations in the fluorescence lifetime of FRET sensors. Moreover, we tracked cell activity across various cycles following co-culture with an immune checkpoint inhibitor. Consequently, we assessed how cell cycle regulation influences immunotherapy in a tumor mouse model. This approach, which involves inhibiting typical cell cycle processes, markedly enhances the effectiveness of immunotherapy. Our findings suggest that modulating the cycle progression of cancer cells may represent a promising approach to enhance the immune response of ovarian cancer cells and the efficacy of immunotherapy based on immune checkpoint inhibitors.

Keywords

• cell cycle
• immunotherapy
• ovarian cancer
• FRET sensor
• FLIM