IAP抑制剂APG-1387通过促进IL-12p40分泌提高MSS肠癌对PD-1抗体响应的机制研究

晚期肠癌95%为微卫星稳定型（MSS），对PD-1抗体无效，高通量数据库筛选提示IAP抑制剂有免疫调节作用，其与PD-1抗体在MSS肠癌中的作用和机制尚不清楚。APG-1387是本团队研发的IAP抑制剂，前期临床及动物实验发现其联合PD-1抗体显著抑制肠癌生长；APG-1387治疗后患者外周血IL-12p40增加，抗p40抗体可拮抗其与PD-1抗体的协同作用；APG-1387能激活效应T细胞，增加肿瘤周围NK细胞浸润，促进IFN-γ分泌。我们推测其通过促进IL-12p40分泌正向调节肿瘤免疫微环境，提高MSS肠癌对PD-1抗体的响应。我们将系统研究APG-1387促进IL-12p40分泌的机制，阐明IL-12p40在APG-1387调节肿瘤免疫微环境中的作用，增加动物模型并开展II期临床研究验证其与PD-1抗体的联合作用，寻找疗效预测指标。为MSS肠癌患者提供有效的免疫联合方案，改善预后。

Among metastatic colon cancer patients, 95% are microsatellite stable (MSS), which have no effect to PD-1 antibody. High-Throughput Immunomodulator Phenotypic Screening Platform (HTiP) suggests that IAP inhibitors have immunomodulatory effect. The role and mechanism of IAP inhibitor and PD-1 antibody in MSS colon cancer patients are still unclear. APG-1387 is an IAP inhibitor developed by our team. In early clinical and animal experiments, we found that the combination of APG-1387 and PD-1 antibody significantly inhibited the growth of colon cancer. The level of IL-12p40 in peripheral blood of patients increased after treatment with APG-1387 single agent, and anti-IL-12p40 antibody could antagonize the synergistic effect of APG-1387 and PD-1 antibody. APG-1387 could activate effector T cells, increase the infiltration of NK cells around the tumor, and promote the secretion of IFN-γ. We speculated that APG-1387 could positively regulate tumor immune microenvironment and enhance the response of MSS colon cancer to PD-1 antibody by promoting IL-12p40 secretion. We will systematically study the mechanism of how APG-1387 promoting the secretion of IL-12p40, clarify the role of IL-12p40 in the regulation of tumor immune microenvironment by APG-1387, and explore the combined effect of APG-1387 and PD-1 antibody in more animal models searching for predictive factors of response. Finally we will carry out a phase II clinical trial to verify our findings. The present study will provide an effective immune combination regimen for MSS colon cancer patients and improve their prognosis.