Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD‐L1)‐mediated immunosuppression
Abstract
Aging is characterized by a progressive loss of physiological integrity, while cancer represents one of the primary pathological factors that severely threaten human lifespan and healthspan. In clinical oncology, drug resistance limits the efficacy of most anticancer treatments, and identification of major mechanisms remains a key to solve this challenging issue. Here, we highlight the multifaceted senescence‐associated secretory phenotype (SASP), which comprises numerous soluble factors including amphiregulin (AREG). Production of AREG is triggered by DNA damage to stromal cells, which passively enter senescence in the tumor microenvironment (TME), a process that remarkably enhances cancer malignancy including acquired resistance mediated by EGFR. Furthermore, paracrine AREG induces programmed cell death 1 ligand (PD‐L1) expression in recipient cancer cells and creates an immunosuppressive TME via immune checkpoint activation against cytotoxic lymphocytes. Targeting AREG not only minimized chemoresistance of cancer cells, but also restored immunocompetency when combined with classical chemotherapy in humanized animals. Our study underscores the potential of in vivo SASP in driving the TME‐mediated drug resistance and shaping an immunosuppressive niche, and provides the proof of principle of targeting major SASP factors to improve therapeutic outcome in cancer medicine, the success of which can substantially reduce aging‐related morbidity and mortality.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 07, 2019
- Source ID
- 10.1111/acel.13027
Entities
People
- Boyi Zhang
- Da Fu
- Dexiang Zhu
- Eric W.‐f. Lam
- Jean‐philippe Coppé
- Jianmin Xu
- Jianming Guo
- Judith Campisi
- Liu Cao
- Liu Han
- Min Qian
- Qilai Long
- Qixia Xu
- Y Sun
- Y. Eugene Chin
Organizations
- Breast Cancer Now
- Buck Institute for Research on Aging
- Cancer Research UK
- Fudan University
- Imperial College London
- Lawrence Berkeley National Laboratory
- Medical Research Council
- National Institute for Health and Care Research
- National Institutes of Health
- National Natural Science Foundation of China
- Shanghai Jiao Tong University
- Soochow University
- Tongji University
- United States Department of Defense
- University of California, San Francisco
- University of Chinese Academy of Sciences
- University of Washington