p53-mediated dead cell clearance in response to DNA damage and tumorigenesis

项目摘要 程序性细胞死亡/凋亡在整个生命过程中发生在身体的所有组织中，并且超过 作为正常过程的一部分，每天有10亿个细胞死亡。从而迅速有效地清除 细胞尸体是维持组织健康的稳态的重要先决条件。未能清除 垂死的细胞会导致自身抗原在组织中的积累， 癌症、慢性炎症、自身免疫和发育异常。 在癌症治疗中，高水平的细胞死亡可以发生在肿瘤环境中，并且 死亡肿瘤细胞被清除的机制影响肿瘤特异性免疫。 因此，操纵死亡细胞去除的免疫学背景对于免疫学治疗具有巨大潜力。 控制肿瘤进展和产生抗肿瘤反应，这仍然是一个挑战。 未解决的问题和了解这一具体机制值得调查。 人们已经为了解肿瘤的各种机制做出了巨大的努力 抑制性p53介导的细胞死亡/凋亡。然而，p53参与后- 细胞凋亡迄今尚未涉及。在这个应用程序中，我们确定了第一个职位- 凋亡靶基因p53，死亡结构域1 α，DD 1 α，这是高度反应的遗传毒性 压力/DNA损伤。我们发现，p53通过其靶点控制凋亡细胞的清除， DD 1 α，表明p53促进了促凋亡途径和凋亡后途径。 事件此外，DD 1 α似乎是一种负性免疫检查点调节剂， 调节免疫应答/T细胞功能，表明DD 1 α在免疫耐受中的作用。 DD 1 α与IgV免疫球蛋白超家族的几个成员具有相似性 结构域，包括TIM家族蛋白和免疫检查点共抑制剂PD-1和PD-L1。的 公共数据库表明DD 1 α的表达在多种人类癌症中增加， 暗示其在癌症中的免疫调节功能。根据这些数据，我们提出了两个 主要目的集中在理解新发现的凋亡后细胞因子的作用机制上。 p53的靶点，并研究增强抗肿瘤免疫应答的潜力。

Project Summary Programmed cell death/apoptosis occurs throughout life in all tissues of the body and more than a billion of cells die everyday as part of normal processes. Thus rapid and efficient clearance of cell corpses is a vital prerequisite for homeostatic maintenance of tissue health. Failure to clear dying cells can lead to the accumulation of autoantigens in tissues that foster diseases such as cancer, chronic inflammation, autoimmunity and developmental abnormalities. High level of cell death can occur within tumor environment in cancer therapy, and the mechanisms through which dying tumor cells are cleared influence tumor-specific immunity. Thus, manipulation of the immunological context of dead cell removal has great potential for the control of tumor progression and generation of an antitumor response, which is still an outstanding issue and understanding this specific mechanism warrants investigation. Enormous efforts have been made toward understanding various mechanisms of tumor suppressor p53-mediated cell death/apoptosis. However, the involvement of p53 in post- apoptosis has not been implicated until now. In this application, we identified a first post- apoptotic target gene of p53, death domain1α, DD1α, which is highly responsive to genotoxic stresses/DNA damage. We found that p53 controls apoptotic cell clearance of through its target DD1α, suggesting that p53 promotes both the pro-apoptotic pathway and the post-apoptotic events. Moreover, DD1α appears to function as a negative immune-checkpoint regulator that modulates immune responses/T cell function, suggesting the role of DD1α in immune tolerance. DD1α has similarity with several members of the immunoglobulin superfamily with the IgV domain, including TIM family proteins and immune checkpoint co-inhibitors PD-1 and PD-L1. The public database indicates that expression of DD1α is increased in multiple human cancers, implicating its immune modulating function in cancer. Based on these data, we propose two major aims focused on mechanisms of understanding the roles of a newly found post-apoptotic target of p53 and investigating the potential to enhance the anti-tumor immune responses.