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力

IF 25.5 1区 医学 Q1 IMMUNOLOGY
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, Paulo C. Rodriguez
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引用次数: 0

摘要

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。在此,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。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。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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

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 JAG2 in NSCLC negatively correlated with survival. In NSCLC pre-clinical models, deletion of Jag2, but not Jag1, 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, 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 transcription factor IRF4 and macrophage immunostimulatory functionality. IRF4 expression was required for the anti-tumor effects of Jag2 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.

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来源期刊
Immunity
Immunity 医学-免疫学
CiteScore
49.40
自引率
2.20%
发文量
205
审稿时长
6 months
期刊介绍: Immunity is a publication that focuses on publishing significant advancements in research related to immunology. We encourage the submission of studies that offer groundbreaking immunological discoveries, whether at the molecular, cellular, or whole organism level. Topics of interest encompass a wide range, such as cancer, infectious diseases, neuroimmunology, autoimmune diseases, allergies, mucosal immunity, metabolic diseases, and homeostasis.
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