Ronen Daniel, Bsoul Aseel, Lotem Michal, Abedat Suzan, Yarkoni Merav, Amir Offer, Asleh Rabea
Department of Internal Medicine D, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
Cardiovascular Research Center, Heart Institute, Hadassah University Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
Vaccines (Basel). 2022 Mar 31;10(4):540. doi: 10.3390/vaccines10040540.
Adaptive immune response modulation has taken a central position in cancer therapy in recent decades. Treatment with immune checkpoint inhibitors (ICIs) is now indicated in many cancer types with exceptional results. The two major inhibitory pathways involved are cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and programmed cell death protein 1 (PD-1). Unfortunately, immune activation is not tumor-specific, and as a result, most patients will experience some form of adverse reaction. Most immune-related adverse events (IRAEs) involve the skin and gastrointestinal (GI) tract; however, any organ can be involved. Cardiotoxicity ranges from arrhythmias to life-threatening myocarditis with very high mortality rates. To date, most treatments of ICI cardiotoxicity include immune suppression, which is also not cardiac-specific and may result in hampering of tumor clearance. Understanding the mechanisms behind immune activation in the heart is crucial for the development of specific treatments. Histological data and other models have shown mainly CD4 and CD8 infiltration during ICI-induced cardiotoxicity. Inhibition of CTLA4 seems to result in the proliferation of more diverse T0cell populations, some of which with autoantigen recognition. Inhibition of PD-1 interaction with PD ligand 1/2 (PD-L1/PD-L2) results in release from inhibition of exhausted self-recognizing T cells. However, CTLA4, PD-1, and their ligands are expressed on a wide range of cells, indicating a much more intricate mechanism. This is further complicated by the identification of multiple co-stimulatory and co-inhibitory signals, as well as the association of myocarditis with antibody-driven myasthenia gravis and myositis IRAEs. In this review, we focus on the recent advances in unraveling the complexity of the mechanisms driving ICI cardiotoxicity and discuss novel therapeutic strategies for directly targeting specific underlying mechanisms to reduce IRAEs and improve outcomes.
近几十年来，适应性免疫反应调节在癌症治疗中占据了核心地位。免疫检查点抑制剂（ICI）治疗目前已被应用于多种癌症类型，并取得了显著疗效。其中涉及的两条主要抑制途径是细胞毒性T淋巴细胞相关蛋白4（CTLA4）和程序性细胞死亡蛋白1（PD-1）。不幸的是，免疫激活并非肿瘤特异性的，因此，大多数患者会经历某种形式的不良反应。大多数免疫相关不良事件（IRAE）累及皮肤和胃肠道；然而，任何器官都可能受累。心脏毒性范围从心律失常到危及生命的心肌炎，死亡率非常高。迄今为止，大多数ICI心脏毒性的治疗方法包括免疫抑制，而免疫抑制也不是心脏特异性的，可能会导致肿瘤清除受阻。了解心脏免疫激活背后的机制对于开发特异性治疗方法至关重要。组织学数据和其他模型显示，ICI诱导的心脏毒性过程中主要有CD4和CD8浸润。抑制CTLA4似乎会导致更多样化的T0细胞群体增殖，其中一些具有自身抗原识别能力。抑制PD-1与PD配体1/2（PD-L1/PD-L2）的相互作用会导致耗尽的自我识别T细胞从抑制中释放出来。然而，CTLA4、PD-1及其配体在多种细胞上表达，这表明机制更为复杂。多种共刺激和共抑制信号的识别，以及心肌炎与抗体驱动的重症肌无力和肌炎IRAE的关联，使情况更加复杂。在本综述中，我们重点关注在揭示驱动ICI心脏毒性机制复杂性方面的最新进展，并讨论直接针对特定潜在机制以减少IRAE和改善治疗结果的新型治疗策略。
