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 Kang,
Hanqiu Zheng
Affiliations
Jingjing Meng
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Yi-zhou Jiang
Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Shen Zhao
Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
Yuwei Tao
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Tengjiang Zhang
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Xuxiang Wang
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Yuan Zhang
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Keyong Sun
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Min Yuan
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
Jin Chen
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
Yong Wei
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA
Xun Lan
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Mo Chen
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Charles J. David
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Zhijie Chang
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Xiaohuan Guo
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Deng Pan
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China
Meng Chen
National Cancer Data Center, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
Zhi-Ming Shao
Department of Breast Surgery, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Corresponding author
Yibin Kang
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA; Cancer Metabolism and Growth Program, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA; Ludwig Institute for Cancer Research, Princeton Branch, Princeton, NJ 08544, USA; Corresponding author
Hanqiu Zheng
Department of Basic Medical Sciences, School of Medicine, Tsinghua University, Beijing 100084, China; Corresponding author
Summary: 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.
