酸浆内酯B抑制IFNG-JAK-CEACAM1通路阻断TIM3介导的胃癌PD1抗体治疗耐药的作用研究

TIM3-mediated severe T-cell exhaustion is the main mechanism of anti-PD1 cancer immunotherapy resistance. Recent studies have shown that inhibition of IFNG-JAK-STAT1 pathway antagonizes the severe T-cell exhaustion that causes acquired resistance to anti-PD1 immunotherapy. Our group discovered a novel JAK inhibitor Physapubescin B (PB) from Chinese herb Physalis alkekengi (a traditional clearing heat and detoxification Chinese medicine). Our preliminary data suggested PB reduced TIM3(+) T cells, a severe T-cell exhaustion sub-population, through inhibiting IFNG-JAK-STAT1-CEACAM1 pathway. We then hypothesize that PB may block TIM3-mediated resistance to anti-PD1 immunotherapy in gastric cancer by repressing the IFNG-JAK-CEACAM1 signaling. We plan to apply technologies such as humanized NSGTM mouse models with gastric cancer xenografts and in situ proximity ligation assay to test this hypothesis. In our proposal, we aim to: (1) clarify the mechanism of PB inhibition of IFNG-JAK-STAT1-CEACAM1 signaling; (2) clarify the molecular mechanism underling how PB inhibits TIM3-mediated severe T-cell exhaustion through CEACAM1 repression; (3) clarify the mechanism of synergistic effect of PB and anti-PD1 immunotherapy for the immune elimination of gastric cancer cells. Our research will not only lay the scientific foundation for the clinical application of such combination therapy, but also provide new direction for future studies on Chinese traditional medicine for cancer immunotherapy.

TIM3介导的效应T细胞重度耗竭在肿瘤抗PD1治疗耐药中发挥重要作用，而抑制IFNG-JAK-STAT1信号通路可阻断抗PD1治疗耐药。我们从清热解毒类中药酸浆中发现新型JAK抑制剂酸浆内酯B，其抑制IFNG-JAK-STAT1-CEACAM1通路，减少TIM3+T细胞比例。基于此，我们提出酸浆内酯B抑制IFNG-JAK-CEACAM1通路阻断TIM3介导的胃癌PD1抗体治疗耐药的科学假设。围绕该假设，我们应用人源化NSGTM小鼠胃癌模型、原位邻位连接分析等技术：⑴揭示酸浆内酯B抑制IFNG-JAK-STAT1-CEACAM1通路的作用机制；⑵阐明酸浆内酯B下调CEACAM1抑制TIM3介导效应T细胞重度耗竭的分子机制；⑶明确酸浆内酯B协同PD1抗体免疫清除胃癌的作用机理。通过本项目研究，不仅为两者联合用药的研发和临床应用提供科学依据，而且为中医药肿瘤免疫治疗提供新思路。

在中医药理论和临床实践的指导下，本课题组应用现代科学方法明确清热解毒类中药酸浆活性成分酸浆内酯B和PD1抗体、酸浆内酯B和MEK抑制剂联合抗胃癌的作用效应和分子机制。明确酸浆内酯B序贯联合PD1抗体、酸浆内酯B联合MEK抑制剂曲美替尼协同抑制小鼠胃癌移植瘤生长的作用，联合治疗抑瘤效果明显，且安全性高。揭示了酸浆内酯B抑制IFNG-JAK通路阻断TIM3介导的效应T细胞重度耗竭，酸浆内酯B抑制单核巨噬细胞和T淋巴细胞NF-κB经典信号通路的活化，以及酸浆内酯B诱导EGFR-ERK通路活化实现曲美替尼的增敏作用的分子机制。通过本项目研究，不仅为两者联合用药的研发和临床应用提供科学依据，而且为中医药肿瘤免疫治疗提供新思路。.资助项目执行期间，发表标注本基金号的SCI论文7篇和核心中文期刊1篇，其中通讯作者发表影响因子大于6分的SCI论文3篇和影响因子大于4分的SCI论文2篇。项目负责人分别作为第二完成人和第三完成人获得教育部高等学校科学技术进步奖二等奖和中国中医药科技进步奖二等奖；项目负责人作为第一发明人授权国家发明专利2项；培养硕士研究生3位。