Tumor-derived Jagged1 promotes cancer progression through immune evasion

Immune checkpoint inhibitor (ICI) therapy is generating remarkable responses in individuals with cancer, but only a small portion of individuals with breast cancer respond well. Here we report that tumor-derived Jagged1 is a key regulator of the tumor immune microenvironment. Jagged1 promotes tumorigenesis in multiple spontaneous mammary tumor models. Through Jagged1-induced Notch activation, tumor cells increase expression and secretion of multiple cytokines to help recruit macrophages into the tumor microenvironment. Educated macrophages crosstalk with tumor-infiltrating T cells to inhibit T cell proliferation and tumoricidal activity. In individuals with triple-negative breast cancer, a high expression level of Jagged1 correlates with increased macrophage infiltration and decreased T cell activity. Co-administration of an ICI PD-1 antibody with a Notch inhibitor significantly inhibits tumor growth in breast cancer models. Our findings establish a distinct signaling cascade by which Jagged1 promotes adaptive immune evasion of tumor cells and provide several possible therapeutic targets. [Display omitted] •Tumor-derived Jagged1 promotes breast cancer progression•Notch activation in tumor cells leads to cytokine production and macrophage recruitment•Tumor education macrophages suppress CD8+ T cell proliferation and tumoricidal activity•Co-administration of PD-1 antibody and Notch inhibitor restrains tumor growth in vivo Meng et al. report that tumor-derived Jagged1 helps recruit macrophages and blocks tumor-killing T cell functions to promote tumor immune evasion during breast cancer progression. Co-administration of an immune checkpoint inhibitor and Jagged1-Notch pathway inhibitor restrains tumor growth in vivo.