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

项目摘要 将免疫检查点阻断纳入抗癌药物治疗已经彻底改变了癌症 近年来，FDA批准的药物用于多种癌症类型的治疗。然而，有一个紧迫的 需要确定额外的治疗策略，以提高持久的反应率。诱导免疫原性 细胞死亡就是这样的策略之一。BCL-2家族蛋白是线粒体凋亡的中心调节因子 由（1）多结构域抗凋亡BCL-2、BCL-XL和MCL-1，（2）多结构域促凋亡BAX 和巴克，以及（3）促凋亡的仅BH 3分子（BH 3 s）。BAX和巴克是MOMP的重要效应因子 而BCL-2、BCL-XL和MCL-1保持线粒体完整性。BH 3是死亡哨兵， 上游凋亡信号通过激活BAX/巴克或失活BCL-2/BCL-2启动凋亡。 XL/MCL-1。通过相互作用的相互连接的层次网络，BCL-2家族蛋白质整合 发育和环境线索来决定细胞的存活与死亡决定。研究 BCL-2调节的凋亡途径不仅揭示了其在正常生理和病理过程中的重要性， 疾病过程，而且还导致了第一个针对蛋白质-蛋白质相互作用的抗癌药物。 最近的范式转变发现表明，在没有半胱天冬酶的情况下，BAX/巴克激活可以 通过一个称为“线粒体内分泌”的过程， 膜透化”（MIMP），其继而激活cGAS/STING途径和I型干扰素 反应因此，BCL-2家族不仅在决定细胞存活或自杀方面起着至关重要的作用， 而且决定以免疫沉默或炎症的方式死亡。MIMP的发现和 它在激活免疫原性细胞死亡中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的分子和生物化学基础仍然是未知的。此外，尚不清楚 肿瘤中MIMP的诱导是否会影响肿瘤免疫串扰和免疫治疗反应。在 在这项拨款申请中，我们制定了一个全面的计划，以询问生物化学和分子生物学。 MIMP的基础上，并开发MIMP作为治疗策略，以改善和加强免疫治疗。我们 这些研究不仅将为BCL-2调节的细胞死亡程序提供新的机制见解， 为靶向BCL-2家族诱导免疫原性细胞死亡奠定基础， 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.