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. [Display omitted] •Lung tumors expressing Jagged2 associate with poor outcome and immune evasion•Jagged2 deletion in lung tumors primes expansion of immunostimulatory macrophages•DLL1/4 in Jagged2-null tumors rewires macrophage function via Notch1/2-induced IRF4•Anti-Jagged2 therapy promotes anti-tumor responses through IRF4-driven macrophages Signaling via Notch receptors intrinsically regulates tumor cells, promoting tumor progression. Mandula et al. examine the impact of Notch ligands on cancer cells on anti-tumor immunity in lung cancer and find that deletion of Jagged2 promotes expansion of immunostimulatory macrophages and anti-tumor T cell immunity. Mechanistically, in the absence of Jagged2, the Notch ligand DLL1/4 on tumor cells rewires macrophages via Notch-mediated induction of the transcription factor IRF4.