Dual blockades of TIM-3 and PD-1 effectively prevent hyper-progression and enhance the efficacy of anti-PD-1 therapy in high-grade serous ovarian cancer

The programmed cell death 1 (PD-1), exhibits limited efficacy in high-grade serous ovarian cancer (HGSOC), with an average response rate of 10 to 15%. Furthermore, hyper-progression disease (HPD), which mostly occurs under immune checkpoint blockade (ICB) therapy, is a potentially deleterious side effect of ICB therapy that accelerates disease progression in HGSOC patients. Our study aims to identify the approach to improve the efficacy of anti-PD-1 treatment on HGSOC in preclinical settings. The prominent TIM-3 upregulation in CD8⁺ tumor-infiltrating lymphocytes (TILs) and tumor-infiltrating dendritic cells (TIDCs) and the phenomenon of HPD were observed in ID8_VEGF-bearing mice after anti-PD-1 treatment. TIM-3 and PD-1 co-blockades prevented the occurrence of HPD in pre-clinical models and prolonged their survival. Meanwhile, TIM-3 and PD-1 co-blockades effectively enhanced the function and proliferation of CD8⁺TILs and TIDCs from ID8_VEGF-bearing mice. Notably, TIM-3 and PD-1 inhibitors effectively enhanced the anti-tumor immunity of CD8⁺TILs and CD11c⁺ myeloid cells from HGSOC patients. Our study uncovers the significance of TIM-3 inhibition in preventing the occurrence of HPD and enhancing the efficacy of anti-PD-1 therapy in HGSOC.