Signaling through Notch receptors intrinsically regulates tumor cell development and growth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion in non-small cell lung cancer (NSCLC). Higher expression of in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of , but not , in cancer cells attenuated tumor growth and activated protective anti-tumor T cell responses. Jag2 lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatory mediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, ablation promoted Nr4a-mediated induction of Notch ligands DLL1/4 on cancer cells. DLL1/4-initiated Notch1/2 signaling in macrophages induced the expression of transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth and activated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediated anti-tumor immunity.

中文翻译：

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肺癌中的 Jagged2 靶向通过 Notch 诱导的肿瘤相关巨噬细胞功能重编程激活抗肿瘤免疫

通过 Notch 受体发出的信号从本质上调节肿瘤细胞的发育和生长。在这里，我们研究了 Notch 配体 Jagged2 在非小细胞肺癌 (NSCLC) 免疫逃避中的作用。 NSCLC 中较高的表达与生存呈负相关。在 NSCLC 临床前模型中，癌细胞中 的删除，但不是 的删除，会减弱肿瘤生长并激活保护性抗肿瘤 T 细胞反应。 Jag2 肺部肿瘤表现出更高频率的巨噬细胞，这些巨噬细胞表达免疫刺激介质并触发 T 细胞依赖性抗肿瘤免疫。从机制上讲，消融促进了癌细胞上 Nr4a 介导的 Notch 配体 DLL1/4 的诱导。巨噬细胞中 DLL1/4 启动的 Notch1/2 信号传导诱导转录因子 IRF4 的表达和巨噬细胞免疫刺激功能。 IRF4 表达是肺肿瘤中缺失的抗肿瘤作用所必需的。 Jagged2 抗体靶向抑制肿瘤生长并激活 IRF4 驱动的巨噬细胞介导的抗肿瘤免疫。因此，Jagged2 在 NSCLC 中协调免疫抑制系统，可以克服该系统来激发巨噬细胞介导的抗肿瘤免疫。