美国H. 李-莫菲特癌症中心Paulo C. Rodriguez研究团队发现，肺癌中的Jagged2靶向药物通过Notch诱导的肿瘤相关巨噬细胞功能重编程激活抗肿瘤免疫。相关论文于2024年4月17日在线发表在《免疫》杂志上。

研究人员揭示了Notch配体Jagged2在非小细胞肺癌（NSCLC）免疫逃避中的作用。JAG2在NSCLC中的高表达与生存率呈负相关。在NSCLC临床前模型中，癌细胞中Jag2（而非Jag1）的缺失可减轻肿瘤生长并激活保护性抗肿瘤T细胞反应。Jag2^-/-肺肿瘤显示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。

从机理上讲，Jag2消减促进了Nr4a介导的Notch配体DLL1/4对癌细胞的诱导。巨噬细胞中由DLL1/4启动的Notch1/2信号诱导了转录因子IRF4的表达和巨噬细胞的免疫刺激功能。肺部肿瘤中Jag2缺失的抗肿瘤作用需要IRF4的表达。以Jagged2为靶点的抗体可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中协调了免疫抑制系统，该系统可被克服以激发巨噬细胞介导的抗肿瘤免疫。

据悉，通过Notch受体发出的信号本质上调控着肿瘤细胞的发育和生长。

附：英文原文

Title: Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages

Author: Jay K. Mandula, Rosa A. Sierra-Mondragon, Rachel V. Jimenez, Darwin Chang, Eslam Mohamed, Shiun Chang, Julio A. Vazquez-Martinez, Yu Cao, Carmen M. Anadon, Sae Bom Lee, Satyajit Das, Léo Rocha-Munguba, Vincent M. Pham, Roger Li, Ahmad A. Tarhini, Muhammad Furqan, William Dalton, Michelle Churchman, Carlos M. Moran-Segura, Jonathan Nguyen, Bradford Perez, Douglas J. Kojetin, Alyssa Obermayer, Xiaoqing Yu, Ann Chen, Timothy I. Shaw, Jose R. Conejo-Garcia, Paulo C. Rodriguez

Issue&Volume: 2024-04-17

Abstract: Signaling through Notch receptors intrinsically regulates tumor cell development andgrowth. Here, we studied the role of the Notch ligand Jagged2 on immune evasion innon-small cell lung cancer (NSCLC). Higher expression of JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletionof Jag2, but not Jag1, in cancer cells attenuated tumor growth and activated protective anti-tumor T cellresponses. Jag2/ lung tumors exhibited higher frequencies of macrophages that expressed immunostimulatorymediators and triggered T cell-dependent anti-tumor immunity. Mechanistically, Jag2 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 transcriptionfactor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was requiredfor the anti-tumor effects of Jag2 deletion in lung tumors. Antibody targeting of Jagged2 inhibited tumor growth andactivated IRF4-driven macrophage-mediated anti-tumor immunity. Thus, Jagged2 orchestrates immunosuppressive systems in NSCLC that can be overcome to incite macrophage-mediatedanti-tumor immunity.

DOI: 10.1016/j.immuni.2024.03.020

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00141-9