Xi Li

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

Abstract 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.

Curcumin suppresses malignant behaviors of ovarian cancer through regulation of tumor-associated macrophages

Curcumin, a natural polyphenol with established anti-tumor properties, has shown therapeutic potential in ovarian cancer. However, its mechanisms, particularly through modulation of tumor-associated macrophages (TAMs) in the tumor microenvironment, remain unexplored. This study aimed to elucidate how curcumin suppresses ovarian cancer progression by regulating TAM polarization. Primary TAMs isolated from ascites of ovarian cancer patients were co-cultured with SKOV3/OVCAR-3 cancer cells. Curcumin was administered at varying doses (5-80 μM) to assess its direct effects on cancer cell viability and its indirect effects via TAM modulation. Epithelial-mesenchymal transition (EMT), migration, invasion, and cytokine profiles were analyzed using CCK-8, flow cytometry, RT-PCR, Western blot, and functional assays. High-dose curcumin (40-80 μM) directly inhibited cancer cell proliferation. In contrast, low-dose curcumin (5-20 μM) suppressed TAM-induced malignant behaviors: it reduced M2 polarization (CD206⁺ TAMs decreased by 54.89% to 32.14%, p < 0.01) while increasing M1-associated cytokines (IL-12↑, IL-1β↑) and decreasing M2 markers (IL-10↓, TGF-β↓). TAM-conditioned medium primed with 20 μM curcumin significantly attenuated cancer cell migration (scratch closure: 65% vs. 85% in TAM-only group, p < 0.01), invasion, and EMT (E-cadherin↑, N-cadherin↓, Vimentin↓). Our study uncovered the mechanism of the anti-tumor effect of curcumin in low doses related to the regulation of TAMs, which might provide novel insight into the treatment of ovarian cancer.