作者
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,Das S,Léo Rocha-Munguba,Vincent N. Pham,Roger Li,Ahmad A. Tarhini,Muhammad Furqan,William S. Dalton,Michelle L. Churchman,Carlos Moran‐Segura,Jonathan V. Nguyen,Bradford A. Perez,D.J. Kojetin,Alyssa Obermayer,Xiaoqing Yu,Ann Chen,Timothy I. Shaw,José R. Conejo-García,Paulo C. Rodríguez
摘要
Summary
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.