@article{6ee1b702a4914db38e0a6cf27ff6a72c,
title = "Tumor-derived Jagged1 promotes cancer progression through immune evasion",
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.",
keywords = "CD8 T cell, Jagged1, Notch, breast cancer, immune checkpoint inhibitor, macrophage, tumor microenvironment",
author = "Jingjing Meng and Jiang, {Yi zhou} and Shen Zhao and Yuwei Tao and Tengjiang Zhang and Xuxiang Wang and Yuan Zhang and Keyong Sun and Min Yuan and Jin Chen and Yong Wei and Xun Lan and Mo Chen and David, {Charles J.} and Zhijie Chang and Xiaohuan Guo and Deng Pan and Meng Chen and Shao, {Zhi Ming} and Yibin Kang and Hanqiu Zheng",
note = "Funding Information: The study was partially supported by the National Key Research and Development Program of China ( 2020YFA0509400 to H.Z.), the National Science Foundation of China ( 81772981 and 81972462 to H.Z.), the Tsinghua-Peking Center for Life Sciences (to H.Z.). This study was also supported by the Brewster Foundation, grants from the Breast Cancer Research Foundation, METAvivor, and Susan G. Komen Foundation to Y.K. We thank all members of the Zheng laboratory for helpful discussions and technical assistance. We thank Dr. C. Chen and Dr. Y. Huang for providing the E0771 cell line. We also thank the Laboratory Animal Research Center and the Center of Biomedical Analysis at Tsinghua University for support. Funding Information: The study was partially supported by the National Key Research and Development Program of China (2020YFA0509400 to H.Z.), the National Science Foundation of China (81772981 and 81972462 to H.Z.), the Tsinghua-Peking Center for Life Sciences (to H.Z.). This study was also supported by the Brewster Foundation, grants from the Breast Cancer Research Foundation, METAvivor, and Susan G. Komen Foundation to Y.K. We thank all members of the Zheng laboratory for helpful discussions and technical assistance. We thank Dr. C. Chen and Dr. Y. Huang for providing the E0771 cell line. We also thank the Laboratory Animal Research Center and the Center of Biomedical Analysis at Tsinghua University for support. J.M. and H.Z. performed the experiments. Y.T. T.Z. X.W. and Y.Z. provided experimental assistance for molecular and animal work. Y.-z.J. S.Z. and Z.-M.S. provided clinical samples and performed IHC staining and data analysis. M.C. and J.M. helped with and confirmed the clinical data analysis. K.S. T.Z. and X.L. performed scRNA-seq and data analysis. M.Y. J.C. and Y.W. helped with mouse strain generation and mouse colony maintenance. M.C. C.J.D. and Z.C. helped with Notch signaling analysis in tumor cells and macrophages and helped proofread the manuscript. X.G. and D.P. helped with the in vivo immune cell depletion assay and in vitro cytotoxic T cell killing assay. H.Z. and Y.K. developed the concept, designed the experiments, and supervised the overall study. H.Z. Y.K. and J.M. analyzed the data and wrote and revised the manuscript. The authors declare no conflict of interests in this study. Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = mar,
day = "8",
doi = "10.1016/j.celrep.2022.110492",
language = "English (US)",
volume = "38",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}