细胞焦亡参与IFNγ对肝癌靶向药物Sorafenib增敏作用的研究

Sorafenib是目前最主要的用于晚期肝癌治疗的靶向药物，但其临床疗效并不理想且多数患者对治疗不敏感。申请人的前期研究发现干扰素-γ（IFNγ）对sorafenib具有增敏作用。在多种人肝癌细胞中IFNγ显著增强sorafenib诱导的caspase 3和GSDME依赖的细胞焦亡，而后者可能受到BCL2L14的调控。在此基础上，本项目计划研究：1）IFNγ对sorafenib的体内增敏作用；2）BCL2L14在IFNγ和sorafenib联合诱导细胞焦亡中的作用机制。由于IFNγ是CD8+ T细胞的主要效应性因子且会在免疫治疗中被大量活化，我们发现抗原特异性的CD8+ T细胞和sorafenib能够协同杀伤肿瘤细胞，因此推测免疫治疗能够增强sorafenib的疗效。本研究也将评估3）PD-1抗体和sorafenib联合治疗的抗瘤活性，从而为肝癌的免疫治疗与靶向药物的联合应用奠定理论基础。

Sorafenib is the most widely used targeted therapy for patients with advanced hepatocellular carcinoma. As a multi-tyrosine kinase inhibitor, sorafenib plays antitumor activity through inhibition of both cancer cell proliferation and angiogenesis. However, the therapeutic efficacy of sorafenib is still limited and only a small proportion of patients responds. Our previous study found interferon-γ (IFNγ) could sensitize tumor cells to sorafenib. In several human HCCs, IFNγ enhances sorafenib-induced pyroptosis, which is dependent on caspase 3 and GSDME. Mechanistic study suggests that BCL2L14 upregulated by IFNγ may contribute to increased pyroptosis, because knockdown of BCL2L14 partially reverses cell death induced by IFNγ plus sorafenib. Based on these observations, we propose here to further study: 1) in vivo sensitization mediated by IFNγ signaling to sorafenib; 2) the regulation of BCL2L14 on pyroptosis induced by IFNγ and sorafenib. IFNγ is the major cytokine released by effector T cells and could be largely generated in tumor microenvironment during cancer immunotherapy. We find that antigen-specific CD8+ T cells combined with sorafenib can synergistically induce tumor cell death in co-culture system, thus we speculate that immunotherapy is able to enhance the efficacy of sorafenib in vivo. And here we will evaluate 3) the antitumor efficacy of immunotherapy combined with sorafenib in mouse HCC model. Our study will build a connection between sorafenib sensitivity and tumor immunity, and also establish the theoretical foundation for the combination therapy of immunotherapy plus sorafenib-based targeted therapy in HCC.