PolyIC as an adjuvant outperforms anti-VEGF in combination with anti-PD-L1 therapy in mouse liver tumor models

Background: Immune checkpoint inhibitors combined with antiangiogenic therapy have become the standard of care for advanced HCC, albeit with limited therapeutic benefit. Our previous studies demonstrated the immunomodulatory and antitumor effects of polyIC, a synthetic dsRNA. Here, we compared the efficacy of anti-programmed death ligand 1 (αPD-L1) plus polyIC versus αPD-L1 plus anti-vascular endothelial growth factor (αVEGF) in mouse tumor models. Methods: We established a primary liver tumor model using hydrodynamic tail vein injection of Ras/Myc oncogenes and a metastasized tumor model via intrasplenic injection of colon cancer cells. Flow cytometry and gene expression analysis were performed to assess immune profiles across treatment groups. Key factors contributing to antitumor efficacy were explored. Results: In both models, αPD-L1 plus polyIC demonstrated superior antitumor effects relative to αPD-L1 plus αVEGF. Unlike αVEGF, polyIC enhanced the immune response to αPD-L1 by increasing T cell infiltration, T effector memory CD8 + T cells, CD8 + to CD4 + T cell ratio, and CD8 + T cell function. This combination also promoted apoptosis in tumors and the accumulation of conventional dendritic cells and invariant natural killer T cells. In addition, αPD-L1 plus polyIC treatment led to upregulation of cytokines and chemokines, with CCL5 blockade partially reducing the CD8 + to CD4 + T cell ratio and attenuating polyIC-driven antitumor effects. Conclusions: This preclinical study identifies polyIC as an efficacious adjuvant of αPD-L1 treatment in liver cancer, providing a better strategy to improve immunotherapy outcomes.