Tumor-derived Jagged1 promotes cancer progression through immune evasion.

TitleTumor-derived Jagged1 promotes cancer progression through immune evasion.
Publication TypeJournal Article
Year of Publication2022
AuthorsMeng, J, Jiang, Y-Z, Zhao, S, Tao, Y, Zhang, T, Wang, X, Zhang, Y, Sun, K, Yuan, M, Chen, J, Wei, Y, Lan, X, Chen, M, David, CJ, Chang, Z, Guo, X, Pan, D, Chen, M, Shao, Z-M, Kang, Y, Zheng, H
JournalCell Rep
Volume38
Issue10
Pagination110492
Date Published2022 03 08
ISSN2211-1247
KeywordsHumans, Immune Evasion, Macrophages, Signal Transduction, Triple Negative Breast Neoplasms, Tumor Microenvironment
Abstract

<p>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.</p>

DOI10.1016/j.celrep.2022.110492
Alternate JournalCell Rep
PubMed ID35263601