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

Signaling through Notch receptors intrinsically regulates tumor cell development and growth. However, whether Notch ligands on cancer cells impact anti-tumor immunity remains unclear. We demonstrate that deletion of Notch ligand Jagged2, but not Jagged1, in lung cancer cells attenuates tumor growth and activates anti-tumor T cell responses. Jagged2 deletion in cancer cells incites intra-tumor accumulation of macrophages with elevated capacity to uptake, process, and present antigens. Also, transfer of Jagged2KO tumors-related macrophages into mice provokes lymphocyte-mediated anti-tumor actions, while macrophage ablation in mice restores Jagged2KO tumor growth. Jagged2 deletion on lung tumors induces Notch ligands DLL1/4, which signal through Notch1-2 on macrophages to stimulate IRF4-driven anti-tumor responses. Intercepting DLL1/4 in tumors or IRF4 in myeloid cells blunts macrophage expansion and reinstates Jagged2KO tumor growth. Therapeutically, anti-Jagged2 treatments restrict tumor growth and augment immunotherapy effectiveness. Findings elucidate how cancer cell Jagged2 promotes immune-evasion and identify Jagged2-targeting immunotherapy to activate anti-tumor immunity.