Immune checkpoint inhibitors as senolytic agents.
Immune checkpoint inhibitors as senolytic agents.
复制标题
免疫检查点抑制剂作为抗衰老剂。
DOI：
10.1038/s41422-022-00761-4
复制
发表时间：
2023
期刊：
影响因子：
44.1
通讯作者：
vanDeursen,JanM
中科院分区：
文献类型：
--
作者：
Singh,Parminder;Kapahi,Pankaj;vanDeursen,JanM
衰老，即消除衰老细胞(SNCs)，是治疗衰老和与衰老相关的疾病的一种新的治疗理念，UBX第1325治疗糖尿病黄斑水肿已在临床上首次取得成功。在最近的一篇《自然》杂志的论文中，王等人。现在报道，SNCs的亚群表达PD-L1，并描述了一种新的衰老模式，通过免疫检查点抑制剂清除这些细胞。细胞衰老是一个细胞命运程序，保护哺乳动物免受癌症侵袭，促进组织修复和再生。然而，它也有黑暗的一面，因为组织和器官中积累的衰老细胞(SNC)可能是组织退化和功能障碍的原因。SNCs通过衰老相关分泌表型(SASP)发挥其有益和有害的生物学效应，SASP是一种复杂的异源分泌体，其组成因细胞类型、衰老诱导剂和衰老阶段而异。2在小鼠中进行的概念验证研究表明，衰老和年龄相关疾病的特征是衰老的减慢。3开始寻找药物，选择性和安全地消除与动脉粥样硬化、骨关节炎、肺纤维化、黄斑变性、痴呆症和各种其他疾病有关的有害的SNC。结果表明，病理性SNCs的存活往往依赖于bcl2和bcl2L1，4家族成员的促生存功能，这些蛋白的合成小分子抑制剂在大多数上述疾病的临床前模型中具有有意义的治疗效果。虽然这些抑制剂由于对中性粒细胞和血小板的靶向不良影响而不适合在人体内使用，但它们已被证明在黄斑疾病患者的眼眶内注射时是安全和高效的(NCT04857996)。5具有感官分解特性的天然黄酮类化合物，如栎素(通常与酪氨酸激酶抑制剂达沙替尼结合使用)和非瑟素，也已在临床前模型中进行了广泛的测试。6这些研究中令人鼓舞的结果，加上缺乏明显的不良反应，使这些化合物迅速进入24个临床试验，用于治疗需要全身给药的各种与年龄相关的疾病。这里需要注意的一点是，非瑟素、栎素和达沙替尼的生物学特性高度不同，这将使从感觉化角度解释任何临床效果变得复杂。此外，SNCs可能是高度异质性的，因此未来的治疗可能需要多种模式的清除它们。为了进一步推动感觉神经溶解作为一种治疗概念，Wang和他的同事假设免疫检查点可能在SNC生存中发挥核心作用，如果是这样的话，
Senolysis, the elimination of senescent cells (SNCs), is a novel therapeutic concept for the treatment of aging and agerelated diseases that has scored a first success in the clinic for the treatment of diabetic macular edema with UBX1325. In a recent Nature paper, Wang et al. now report that subsets of SNCs express PD-L1 and describe a novel mode of senolysis through clearance of these cells by immune checkpoint inhibitors.Cellular senescence is a cell fate program that protects mammals against cancer and promotes tissue repair and regeneration. 1 However, it also has a dark side in that senescent cells (SNCs) that accumulate in tissues and organs can be a cause of tissue degeneration and dysfunction. SNCs exert both their beneficial and detrimental biological effects through the senescence-associated secretory phenotype (SASP), a complex heterogenous secretome whose composition varies per cell type, senescence inducer, and senescence stage. 2 Proof-of-concept studies in mice demonstrating that senolysis slows features of aging and age-related diseases 3 initiated a hunt for drugs that selectively and safely eliminate detrimental SNCs implicated in diseases such as atherosclerosis, osteoarthritis, pulmonary fibrosis, macular degeneration, dementia, and various other conditions. It turned out that the viability of pathologycausing SNCs is frequently dependent on the pro-survival functions of BCL family members, particularly BCL2 and BCL2L1, 4 with synthetic small-molecule inhibitors of these proteins having meaningful therapeutic effects in preclinical models of most of the abovementioned diseases. Although these inhibitors are not suitable for systemic use in humans because of on-target adverse effects on neutrophils and thrombocytes, they have been proven to be safe and highly effective upon intraorbital injection in patients with macular disease (NCT04857996). 5 Naturally occurring flavonoids with senolytic properties such as quercetin (typically used in combination with the tyrosine kinase inhibitor dasatinib) and fisetin have also been widely tested in preclinical models. 6 Encouraging results in these studies together with a lack of overt adverse effects allowed these compounds to quickly advance into two dozen clinical trials for a wide variety of age-related disorders that require systemic administration. One key note of caution here is that the biological properties of fisetin, quercetin, and dasatinib are highly diverse, which will complicate the interpretation of any clinical effects in terms of senolysis. Furthermore, SNCs can be highly heterogeneous, and therefore multiple modes of clearing them may be required for future therapeutics. To further advance senolysis as a therapeutic concept, Wang and colleagues hypothesized that the immune checkpoint might play a central role in SNC survival, and if so, that