Tumor-derived Jagged1 promotes cancer progression through immune evasion

Jingjing Meng, Yi zhou Jiang, Shen Zhao, Yuwei Tao, Tengjiang Zhang, Xuxiang Wang, Yuan Zhang, Keyong Sun, Min Yuan, Jin Chen, Yong Wei, Xun Lan, Mo Chen, Charles J. David, Zhijie Chang, Xiaohuan Guo, Deng Pan, Meng Chen, Zhi Ming Shao, Yibin KangHanqiu Zheng

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number110492
JournalCell Reports
Volume38
Issue number10
DOIs
StatePublished - Mar 8 2022

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Keywords

  • CD8 T cell
  • Jagged1
  • Notch
  • breast cancer
  • immune checkpoint inhibitor
  • macrophage
  • tumor microenvironment

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