Functions of mutant IDH in cholangiocarcinoma

项目总结 异柠檬酸脱氢酶1是所有癌症中突变最频繁的代谢基因。在上皮细胞之间 恶性肿瘤，IDH1突变在胆管细胞癌中尤其常见，这是一种致命的肝胆汁癌 风管。这些热点突变产生了肿瘤代谢物(R)-2-羟基戊二酸，它抑制- 依赖酮戊二酸的酶，改变表观遗传学和新陈代谢。而药物的抑制作用 突变的IDH1对胆管癌细胞有疗效，但效果不持久，而且有限 洞察应对和抵抗的基础。最近，通过开发基因驱动的mIDH1 转基因小鼠模型，并利用患者样本和模型，我们证明了mIDH1导致 肿瘤细胞逃避免疫系统的攻击。我们发现突变的IDH1抑制物通过以下方式减缓肿瘤生长 逆转这种免疫逃避表型，导致对免疫检查点阻断的敏化。一位少校 这种逃避的机制涉及(R)-2HG介导的TET2去甲基酶的失活，这 防止肿瘤细胞对免疫细胞产生的干扰素伽马做出反应。第二 机制包括限制细胞毒性T细胞的招募和活性，尽管我们还没有完全 阐明相关的分子基础。根据我们广泛的新的初步数据，我们假设 IDH1介导的细胞分化调控和先天免疫信号是潜在的调节因子 T细胞串扰。目前的建议将检验这一假设，并研究T细胞之间的相互作用 募集和干扰素-g-TET2方案在IDH1抑制剂反应和最终耐药中的作用。这些研究 将为胆管癌的改进治疗提供信息，并可能提供其他癌症类型的范围 携带IDH突变。

PROJECT SUMMARY Isocitrate dehydrogenase 1 is the most frequently mutated metabolic gene across all cancers. Among epithelial malignancies, IDH1 mutations are particularly common in cholangiocarcinoma, a deadly cancer of the liver bile ducts. These hot-spot mutations generate the oncometabolite, (R)-2-hydroxyglutarate, which inhibits - ketoglutarate-dependent enzymes, altering epigenetics and metabolism. While pharmacological inhibition of mutant IDH1 shows efficacy in cholangiocarcinoma, the effects are not durable, and there has been limited insight into the basis for response and resistance. Recently, by developing mIDH1-driven genetically engineered mouse models and utilizing patient samples and models, we demonstrated that mIDH1 causes tumor cells to evade attack by the immune system. We find that inhibitors of mutant IDH1 slow tumor growth by reverting this immune evasion phenotype, leading to sensitization to immune checkpoint blockade. A major mechanism of this evasion involves the (R)-2HG-mediated inactivation of the TET2 demethylase, which prevents the tumor cells from responding to interferon gamma produced by immune cells. The second mechanism involves limiting the recruitment and activity of cytotoxic T cells, although we have yet to fully elucidate the associated molecular basis. Based on our extensive new preliminary data, we hypothesize that IDH1-mediated control of cellular differentiation and of innate immune signaling are potential mediators of this T cell cross-talk. The present proposal will test this hypothesis and investigate the interplay between T cell recruitment and the IFN-g-TET2 program in IDH1 inhibitor response and eventual resistance. These studies will inform the improved treatment of cholangiocarcinoma and potentially the range of other cancer types harboring IDH mutations.