Titin mutation associated with responsiveness to checkpoint blockades in solid tumors
Titin mutation associated with responsiveness to checkpoint blockades in solid tumors
复制标题
肌联蛋白突变与实体瘤检查点阻断的反应相关
DOI：
10.1172/jci.insight.127901
复制
发表时间：
2019-05-16
期刊：
影响因子：
8
通讯作者：
Zhu, Bo
中科院分区：
文献类型：
--
作者：
Jia, Qingzhu;Wang, Jun;Zhu, Bo
免疫检查点阻断（ICB）免疫疗法在多种实体瘤中诱导有效的抗肿瘤免疫，尽管很少有患者对这种疗法反应良好。用于预测对ICB免疫疗法的响应性的新兴生物标志物是肿瘤突变负荷（TMB）。尽管几种替代生物标志物，包括错配修复缺陷，TP 53/KRAS突变和DNA损伤反应途径中的comutations，已被证明可有效预测对检查点阻断免疫治疗的反应，但每种生物标志物仅对一小群候选人呈阳性，并且不可避免地错过了许多对ICB的潜在反应者。在这里，我们发现经常在实体瘤中检测到的肌联蛋白（TTN）与TMB增加相关，并与ICB的客观反应相关。在7个公共临床队列中，所有突变TTN患者的无进展生存期或总生存期均长于野生型患者。此外，在可获得信息的队列中，客观缓解率提高，TMB更高。将TTN突变鉴定为ICB应答结果改善的预测因子，为估计TMB和ICB治疗结果提供了临床可行的评估。
Immune checkpoint blockade (ICB) immunotherapy induces potent antitumor immunity across multiple solid tumors, although few patients respond well to this therapy. An emerging biomarker for predicting responsiveness to ICB immunotherapy is tumor mutational burden (TMB). Although several surrogate biomarkers, including deficient mismatch repair, TP53/KRAS mutations, and comutations in DNA damage response pathways, have been shown to be effective for predicting the response to checkpoint blockade immunotherapy, each is positive for only a small cohort of candidates, and many potential responders to ICB are inevitably missed. Here, we found that titin (TTN), which is frequently detected in solid tumors, is associated with increased TMB and correlated with objective response to ICB. In 7 public clinical cohorts, all patients with mutated TTN showed longer progression-free survival or overall survival than those with wild-type status. Furthermore, an improved objective response rate and higher TMB were identified in cohorts with accessible information. Identification of TTN mutation as a predictor of improved outcomes in response to ICBs provides a clinically feasible assessment for estimating TMB and ICB therapy outcomes.