Persistent inflammation driven by cytokines such as type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the Janus kinase 1 (JAK1) inhibitor itacitinib after anti–PD-1 (programmed cell death protein 1) immunotherapy improves immune function and antitumor responses in mice and results in high response rates (67%) in a phase 2 clinical trial for metastatic non–small cell lung cancer. Patients who failed to respond to initial anti–PD-1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti–PD-1 alone that improved after JAK inhibition. Itacitinib promoted CD8 T cell plasticity and therapeutic responses of exhausted and effector memory–like T cell clonotypes. Patients with persistent inflammation refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve the efficacy of anti–PD-1 immunotherapy by pivoting T cell differentiation dynamics.

中文翻译：

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JAK 抑制和 PD-1 免疫治疗联合治疗非小细胞肺癌患者


由一型干扰素 (IFN-I) 等细胞因子驱动的持续炎症可导致免疫抑制。我们证明，在抗 PD-1（程序性细胞死亡蛋白 1）免疫治疗后给予 Janus 激酶 1 (JAK1) 抑制剂 itacitinib 可改善小鼠的免疫功能和抗肿瘤反应，并在 2 期试验中获得高反应率 (67%)转移性非小细胞肺癌的临床试验。对初始抗 PD-1 免疫疗法没有反应但在添加 itacitinib 后有反应的患者具有多种特征，即单独抗 PD-1 免疫功能较差，但在 JAK 抑制后得到改善。 Itacitinib 可促进 CD8 T 细胞的可塑性以及耗尽型和效应记忆样 T 细胞克隆型的治疗反应。伊塔替尼耐药的持续性炎症患者表现出进行性 CD8 T 细胞终末分化和疾病进展。因此，JAK 抑制可能通过改变 T 细胞分化动力学来提高抗 PD-1 免疫疗法的疗效。