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.

• Authors: 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
• Journal: Cell reports (Cell Rep) Vol. 38 Issue 10 Pg. 110492 (03 08 2022) ISSN: 2211-1247 [Electronic] United States
• PMID: 35263601 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

Topics

• Humans
• Immune Evasion
• Macrophages (metabolism)
• Signal Transduction
• Triple Negative Breast Neoplasms (metabolism)
• Tumor Microenvironment