Ludwig Lindsey M, Nassin Michele L, Hadji Abbas, LaBelle James L
Section of Hematology, Oncology, Stem Cell Transplantation, Department of Pediatrics, University of Chicago, Comer Children's Hospital, Chicago, IL, USA; Committee on Cancer Biology, University of Chicago, Chicago, IL, USA.
Section of Hematology, Oncology, Stem Cell Transplantation, Department of Pediatrics, University of Chicago, Comer Children's Hospital , Chicago, IL , USA.
Front Pediatr. 2016 Dec 21;4:135. doi: 10.3389/fped.2016.00135. eCollection 2016.
A crucial component of regulating organismal homeostasis is maintaining proper cell number and eliminating damaged or potentially malignant cells. Apoptosis, or programed cell death, is the mechanism responsible for this equilibrium. The intrinsic apoptotic pathway is also especially important in the development and maintenance of the immune system. Apoptosis is essential for proper positive and negative selection during B- and T-cell development and for efficient contraction of expanded lymphocytes following an immune response. Tight regulation of the apoptotic pathway is critical, as excessive cell death can lead to immunodeficiency while apoptotic resistance can lead to aberrant lymphoproliferation and autoimmune disease. Dysregulation of cell death is implicated in a wide range of hematological malignancies, and targeting various components of the apoptotic machinery in these cases is an attractive chemotherapeutic strategy. A wide array of compounds has been developed with the purpose of reactivating the intrinsic apoptotic pathway. These compounds, termed BH3 mimetics are garnering considerable attention as they gain greater clinical oncologic significance. As their use expands, it will be imperative to understand the effects these compounds have on immune homeostasis. Uncovering their potential immunomodulatory activity may allow for administration of BH3 mimetics for direct tumor cell killing as well as novel therapies for a wide range of immune-based directives. This review will summarize the major proteins involved in the intrinsic apoptotic pathway and define their roles in normal immune development and disease. Clinical and preclinical BH3 mimetics are described within the context of what is currently known about their ability to affect immune function. Prospects for future antitumor immune amplification and immune modulation are then proposed.
调节机体稳态的一个关键组成部分是维持适当的细胞数量，并清除受损或潜在的恶性细胞。细胞凋亡，即程序性细胞死亡，是维持这种平衡的机制。内源性凋亡途径在免疫系统的发育和维持中也尤为重要。细胞凋亡对于B细胞和T细胞发育过程中适当的阳性和阴性选择，以及免疫反应后扩增淋巴细胞的有效收缩至关重要。严格调控凋亡途径至关重要，因为过度的细胞死亡会导致免疫缺陷，而凋亡抗性会导致异常的淋巴细胞增殖和自身免疫性疾病。细胞死亡失调与多种血液系统恶性肿瘤有关，在这些情况下靶向凋亡机制的各种成分是一种有吸引力的化疗策略。已经开发出了一系列旨在重新激活内源性凋亡途径的化合物。这些化合物被称为BH3模拟物，随着它们在临床肿瘤学上的重要性日益增加，正受到相当多的关注。随着它们的应用范围扩大，了解这些化合物对免疫稳态的影响将变得势在必行。揭示它们潜在的免疫调节活性可能允许使用BH3模拟物直接杀伤肿瘤细胞，以及开发针对广泛基于免疫的指令的新疗法。本综述将总结内源性凋亡途径中涉及的主要蛋白质，并确定它们在正常免疫发育和疾病中的作用。临床和临床前BH3模拟物将在目前已知的它们影响免疫功能能力的背景下进行描述。然后提出未来抗肿瘤免疫增强和免疫调节的前景。
