Characterizing and Targeting BAX- and BAK-Dependent Cell Death in Cancer

项目总结 将免疫检查点阻断纳入抗癌医疗机构使癌症发生了革命性的变化 近年来，FDA批准了多种癌症类型的药物进行治疗。尽管如此，有一项紧急的 需要确定其他治疗策略以提高持久应答率。诱导免疫原性 细胞死亡就是这样一种策略。BCL-2家族蛋白是线粒体凋亡的中枢调节因子 由(1)多结构域抗凋亡的bcl2、bclxl和mcl1组成，(2)多结构域促凋亡的bax 和BAK，以及(3)仅促凋亡的BH3分子(BH3)。BAX和BAK是MOMP的重要效应因子 而BCL-2、BCL-XL和MCL-1则维持线粒体的完整性。BH3是接力的死亡哨兵 上游凋亡信号通过激活Bax/BAK或失活BCL-2/BCL-2来启动细胞凋亡 XL/MCL-1。通过相互连接的层次化相互作用网络，bcl2家族蛋白整合 决定细胞生死决定的发育和环境线索。关于网络安全问题的研究 BCL-2调控的细胞凋亡途径不仅在正常生理和细胞周期中具有重要作用 疾病过程，但也导致了第一个针对蛋白质-蛋白质相互作用的抗癌药物。 最近的范式转换发现表明，在没有caspase的情况下，Bax/BAK的激活可以 触发线粒体DNA释放到胞浆中的过程称为“线粒体内部” 膜通透性“(MIMP)，进而激活cGAS/STING途径和I型干扰素 回应。因此，bcl2家族不仅在细胞生存或自杀的决定中起着至关重要的作用 而且还决定以免疫沉默或炎症的方式死亡。MIMP和MIMP的发现 它在激活免疫原性细胞死亡方面的作用为癌细胞死亡研究开辟了令人兴奋的新途径。 然而，MIMP的分子和生化基础仍不明确。此外，目前还不清楚 MIMP在肿瘤中的诱导是否会影响肿瘤免疫串扰和免疫治疗反应。在……里面 在这次拨款申请中，我们制定了一个全面的计划来审问生化和分子 在MIMP的基础上，开发MIMP作为一种治疗策略，以改进和加强免疫治疗。我们的 研究不仅将为bcl2调控的细胞死亡程序提供新的机制见解，还将 为靶向bcl2家族诱导免疫原性细胞死亡从而增强 癌症免疫疗法。

PROJECT SUMMARY The incorporation of Immune checkpoint blockade into anticancer armamentarium has revolutionized cancer therapy in recent years, with FDA approved agents in multiple cancer types. Nevertheless, there is an urgent need to identify additional therapeutic strategies to increase durable response rates. Induction of immunogenic cell death is one of such strategies. The BCL-2 family proteins are central regulators of mitochondrial apoptosis and consist of (1) multidomain antiapoptotic BCL-2, BCL-XL, and MCL-1, (2) multidomain proapoptotic BAX and BAK, and (3) proapoptotic BH3-only molecules (BH3s). BAX and BAK are the essential effectors of MOMP whereas BCL-2, BCL-XL, and MCL-1 preserve mitochondrial integrity. BH3s are death sentinels that relay upstream apoptotic signals to initiate apoptosis by either activating BAX/BAK or inactivating BCL-2/BCL- XL/MCL-1. Through an interconnected hierarchical network of interactions, the BCL-2 family proteins integrate developmental and environmental cues to dictate the survival versus death decision of cells. The research on the BCL-2-regulated apoptotic pathway has not only revealed its importance in both normal physiological and disease processes, but has also resulted in the first anti-cancer drug targeting protein-protein interactions. Recent paradigm-shifting discoveries have shown that BAX/BAK activation in the absence of caspases can trigger the release of mitochondrial DNA to the cytosol through a process called “mitochondrial inner membrane permeabilization” (MIMP), which in turn activates the cGAS/STING pathway and type I interferon response. Hence, the BCL-2 family plays a crucial role not only in the decision of cells to live or commit suicide but also in the decision to die in an immunologically silent or inflammatory manner. The discovery of MIMP and its role in activating immunogenic cell death opens up exciting new avenues for cancer cell death research. However, the molecular and biochemical basis of MIMP remains uncharacterized. Furthermore, it is unclear whether induction of MIMP in tumors will affect the tumor-immune crosstalk and immunotherapy response. In this grant application, we have formulated a comprehensive plan to interrogate the biochemical and molecular basis of MIMP and exploit MIMP as a therapeutic strategy to improve and enhance immunotherapy. Our studies will not only provide novel mechanistic insights into the BCL-2-regulated cell death program but also lay the foundation for targeting the BCL-2 family to induce immunogenic cell death and thereby enhance cancer immunotherapy.