肝癌免疫治疗的新思路与新策略

This study is to explore new strategy of liver cancer immunotherapy. Despite the great success of immunotherapy in a broad range of cancers, the vast majority of cancer patients showed poor response. Approximately 17% liver cancer patients responded to monotherapy of pembrolizumab and 20% responded to nivolumab. A combination of nivolumab and ipilimumab increased the response rate to 30% in HCC. Simultaneous blockade of PD-L1 and VEGF signaling using atezolizumab and bevacizumab achieved better overall and progression-free survival than sorafenib in HCC. Our previous data showed that monotherapy with anti-PD-L1 antibody exhibited no inhibitory effect in primary liver cancer driven by classical oncogenes in mice. Given a robust induction of PD-L1 expression by polyIC in the liver, we reasoned that the synthetic dsRNA could sensitize hepatic response to alphaPD-L1 treatment. Indeed, combined treatment of polyIC and anti-PD-L1 showed markedly improved efficacy in mouse HCC models. A combinatorial therapy of polyIC and anti-PD-L1 exhibited an intriguing synergistic effect in liver tumors. We interrogated the compositions and changes of immune cell subtypes infiltrated into the tumors grown subcutaneously or in the liver, as well as the whole liver of tumor-bearing mice. The data suggest that it is the tumor microenvironment, rather than the tumor cells, that determine the response to immunotherapy. We have also found that the polyIC+antiPD-L1 combination exhibited more potent anti-tumor effect than antiPD-L1+antiVEGFA. Further, we demonstrate that a monotherapy of liver-targeting lipid nanoparticles that encapsulate polyIC (polyIC-LNP) is sufficient to suppress both primary and metastasized liver tumor progression in mouse models. Current working address: Institute of Cancer Research, Shenzhen Bay Laboratory