Institute of Pathology, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.
Institute for Translational Immunology, Brandenburg Medical School (MHB), Theodor Fontane, Brandenburg an der Havel, Germany.
Front Immunol. 2024 Apr 26;15:1386993. doi: 10.3389/fimmu.2024.1386993. eCollection 2024.
Alternative splicing (AS) is an important molecular biological mechanism regulated by complex mechanisms involving a plethora of cis and trans-acting elements. Furthermore, AS is tissue specific and altered in various pathologies, including infectious, inflammatory, and neoplastic diseases. Recently developed immuno-oncological therapies include monoclonal antibodies (mAbs) and chimeric antigen receptor (CAR) T cells targeting, among others, immune checkpoint (ICP) molecules. Despite therapeutic successes have been demonstrated, only a limited number of patients showed long-term benefit from these therapies with tumor entity-related differential response rates were observed. Interestingly, splice variants of common immunotherapeutic targets generated by AS are able to completely escape and/or reduce the efficacy of mAb- and/or CAR-based tumor immunotherapies. Therefore, the analyses of splicing patterns of targeted molecules in tumor specimens prior to therapy might help correct stratification, thereby increasing therapy success by antibody panel selection and antibody dosages. In addition, the expression of certain splicing factors has been linked with the patients' outcome, thereby highlighting their putative prognostic potential. Outstanding questions are addressed to translate the findings into clinical application. This review article provides an overview of the role of AS in (tumor) diseases, its molecular mechanisms, clinical relevance, and therapy response.
选择性剪接 (AS) 是一种重要的分子生物学机制，受涉及众多顺式和反式作用元件的复杂机制调控。此外，AS 具有组织特异性，并在各种病理情况下发生改变，包括感染、炎症和肿瘤性疾病。最近开发的免疫肿瘤学疗法包括针对免疫检查点 (ICP) 分子的单克隆抗体 (mAb) 和嵌合抗原受体 (CAR) T 细胞等。尽管已经证明了治疗的成功，但只有少数患者从这些疗法中获得了长期益处，观察到与肿瘤实体相关的差异反应率。有趣的是，由 AS 产生的常见免疫治疗靶点的剪接变体能够完全逃避和/或降低基于 mAb 和/或 CAR 的肿瘤免疫疗法的疗效。因此，在治疗前分析肿瘤标本中靶向分子的剪接模式可能有助于正确分层，从而通过抗体组选择和抗体剂量增加治疗的成功率。此外，某些剪接因子的表达与患者的预后相关，从而突出了它们潜在的预后潜力。目前仍存在一些悬而未决的问题，需要将这些发现转化为临床应用。本文综述了 AS 在（肿瘤）疾病中的作用、分子机制、临床相关性和治疗反应。
