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.