Division of Population Sciences, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
Division of Genetics, Brigham & Women's Hospital, Boston, Massachusetts, USA.
Immunol Rev. 2023 Sep;318(1):138-156. doi: 10.1111/imr.13253. Epub 2023 Jul 28.
Cancer immunotherapy has revolutionized the treatment of advanced cancers and is quickly becoming an option for early-stage disease. By reactivating the host immune system, immunotherapy harnesses patients' innate defenses to eradicate the tumor. By putatively similar mechanisms, immunotherapy can also substantially increase the risk of toxicities or immune-related adverse events (irAEs). Severe irAEs can lead to hospitalization, treatment discontinuation, lifelong immune complications, or even death. Many irAEs present with similar symptoms to heritable autoimmune diseases, suggesting that germline genetics may contribute to their onset. Recently, genome-wide association studies (GWAS) of irAEs have identified common germline associations and putative mechanisms, lending support to this hypothesis. A wide range of well-established GWAS methods can potentially be harnessed to understand the etiology of irAEs specifically and immunotherapy outcomes broadly. This review summarizes current findings regarding germline effects on immunotherapy outcomes and discusses opportunities and challenges for leveraging germline genetics to understand, predict, and treat irAEs.
癌症免疫疗法彻底改变了晚期癌症的治疗方法，并且正在迅速成为早期疾病的治疗选择。通过重新激活宿主免疫系统，免疫疗法利用患者的先天防御能力来消灭肿瘤。通过推测的类似机制，免疫疗法还可以大大增加毒性或免疫相关不良事件 (irAE) 的风险。严重的 irAE 可导致住院、治疗中断、终身免疫并发症，甚至死亡。许多 irAE 的表现与遗传性自身免疫性疾病相似，这表明种系遗传学可能促成了其发病。最近，irAE 的全基因组关联研究 (GWAS) 确定了常见的种系关联和潜在的机制，为这一假设提供了支持。广泛的成熟 GWAS 方法都可能被用来了解 irAE 的病因以及免疫疗法的结果。这篇综述总结了目前关于种系对免疫疗法结果的影响的研究结果，并讨论了利用种系遗传学来了解、预测和治疗 irAE 的机会和挑战。
