Department of Clinical Nutrition & Health Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
Inflamm Res. 2024 Feb;73(2):263-276. doi: 10.1007/s00011-023-01833-w. Epub 2024 Jan 10.
Janus kinase 2 (JAK2) mutation plays an important role in T cell immunity. However, the effect of JAK2 mutation on immunotherapy is largely uncharacterized.
In this study, we analyzed the effect of JAK2 mutation on the efficacy and outcomes of immune checkpoint inhibitor (ICI) therapy in the discovery cohort (n = 662) and the verification cohort (n = 1423). Furthermore, we explored the association of JAK2 mutation with the tumor immune microenvironment in a multiomics cohort.
In the discovery cohort (n = 662), JAK2 mutant-type patients had a better objective response rate (58.8% vs. 26.7%, P = 0.010), durable clinical benefit (64.7% vs. 38.9%, P = 0.043), progression-free survival (hazard ratio [HR] = 0.431, P = 0.015), and overall survival (HR = 0.378, P = 0.025), relative to JAK2 wild-type patients. Moreover, we further verified the prognostic significance of JAK2 mutation in an independent ICI treatment cohort with a larger sample size (n = 1423). In addition, we discovered that the JAK2 mutation was remarkably related to increased immunogenicity, such as a higher TMB, higher expression of costimulatory molecules and stimulation of antigen processing mechanisms. In addition, JAK2 mutation was positively correlated with activated anticancer immunity, such as infiltration of various immune cells and higher expression of chemokines.
Our study demonstrates that JAK2 mutation is a novel marker that can be used to effectively predict prognosis and response to ICI therapy.
Janus 激酶 2（JAK2）突变在 T 细胞免疫中起着重要作用。然而，JAK2 突变对免疫疗法的影响在很大程度上尚未得到阐明。
在这项研究中，我们分析了 JAK2 突变对免疫检查点抑制剂（ICI）治疗在发现队列（n = 662）和验证队列（n = 1423）中的疗效和结局的影响。此外，我们还在一个多组学队列中探索了 JAK2 突变与肿瘤免疫微环境的关联。
在发现队列（n = 662）中，JAK2 突变型患者的客观缓解率（58.8%比 26.7%，P = 0.010）、持久的临床获益（64.7%比 38.9%，P = 0.043）、无进展生存期（风险比[HR] = 0.431，P = 0.015）和总生存期（HR = 0.378，P = 0.025）均优于 JAK2 野生型患者。此外，我们在一个具有更大样本量的独立 ICI 治疗队列中进一步验证了 JAK2 突变的预后意义（n = 1423）。此外，我们发现 JAK2 突变与免疫原性增加显著相关，例如更高的 TMB、共刺激分子的更高表达和刺激抗原加工机制。此外，JAK2 突变与激活的抗癌免疫呈正相关，例如各种免疫细胞的浸润和趋化因子的更高表达。
我们的研究表明，JAK2 突变是一种新的标志物，可以有效地预测预后和对 ICI 治疗的反应。
