The majority of T-cell responses involve proteasome-dependent protein degradation and the downstream presentation of oligopeptide products complexed with major histocompatibility complex (MHC) class I (MHC-I) molecules to peptide-restricted CD8+T-cells. However, evasion of host immunity is a cancer hallmark that is achieved by disruption of host antigen processing and presentation machinery (APM). Consequently, mechanisms of immune evasion promote cancer growth and survival as well as de novo and acquired resistance to immunotherapy. A multitude of cell signaling pathways modulate the APM and MHC-I-dependent antigen presentation. Pharmacologics that specifically target and modulate proteasome structure and activity represent a novel emerging strategy to improve the treatment of cancers and other diseases characterized by aberrant protein accumulation. FDA-approved pharmacologics that selectively activate proteasomes and/or immunoproteasomes can be repositioned to overcome the current bottlenecks that hinder drug development to enhance antigen presentation, modulate the immunopeptidome, and enhance the cytotoxic activity of endogenous or engineered T-cells. Strategies to enhance antigen presentation may also improve the antitumor activity of T-cell immunotherapies, checkpoint inhibitors, and cancer vaccines. Proteasomes represent actionable therapeutic targets to treat difficult-to-treat infectious processes and neurodegenerative diseases that are characterized by the unwanted accrual of insoluble, deleterious, and potentially toxic proteins. Taken together, we highlight the breadth and magnitude of the proteasome and the immense potential to amplify and unmask the immunopeptidomic landscape to improve the treatment of a spectrum of human diseases.
大多数T细胞应答涉及蛋白酶体依赖性蛋白降解，以及随后形成的寡肽产物与主要组织相容性复合体I类分子结合，并呈递给肽段限制性CD8+T细胞。然而，逃避宿主免疫是癌症的一个标志性特征，其通过破坏宿主抗原加工与呈递机制实现。因此，免疫逃逸机制不仅促进肿瘤生长和存活，还导致对免疫治疗的原发性和获得性耐药。多种细胞信号通路调控抗原加工呈递机制及MHC-I依赖性抗原呈递。特异性靶向并调控蛋白酶体结构与活性的药物代表了一种新兴策略，可用于改善以异常蛋白累积为特征的癌症及其他疾病的治疗。经FDA批准的能选择性激活蛋白酶体和/或免疫蛋白酶体的药物可被重新定位，以克服当前阻碍药物开发的瓶颈，从而增强抗原呈递、调控免疫肽组并提升内源性或工程化T细胞的细胞毒活性。增强抗原呈递的策略也可能改善T细胞免疫疗法、检查点抑制剂和癌症疫苗的抗肿瘤活性。蛋白酶体可作为可操作的治疗靶点，用于治疗以不溶性、有害及潜在毒性蛋白异常累积为特征的难治性感染过程和神经退行性疾病。综上所述，我们强调蛋白酶体作用的广度与深度，以及其在拓展和揭示免疫肽组学景观方面的巨大潜力，这将为一系列人类疾病的治疗带来革新。
肿瘤(癌症)患者之家