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.

Automated summary

This study reveals that Jagged1, derived from tumors, plays a crucial role in regulating the immune microenvironment of breast cancer. Jagged1 promotes tumorigenesis and facilitates the recruitment of macrophages into the tumor microenvironment by activating the Notch pathway. Educated macrophages then interact with tumor-infiltrating T cells to inhibit their proliferation and tumoricidal activity. The high expression of Jagged1 in triple-negative breast cancer patients is associated with increased macrophage infiltration and decreased T cell activity. Co-administration of an ICI PD-1 antibody with a Notch inhibitor effectively inhibits tumor growth in breast cancer models, suggesting potential therapeutic targets.