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Title: 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.

Authors:
 [1];  [2];  [2];  [3];  [1];  [1];  [1];  [2];  [2];  [4];  [5];  [6];  [7];  [8]; ORCiD logo [9]
  1. Chinese Academy of Sciences (CAS), Shanghai (China)
  2. Fudan Univ., Shanghai (China)
  3. Tongji Univ. School of Medicine, Shanghai (China)
  4. China Medical Univ., Shenyang (China)
  5. Soochow Univ. Medical College, Suzhou, Jiangsu (China)
  6. Univ. of California, San Francisco, CA (United States)
  7. Imperial College, London (United Kingdom)
  8. Buck Inst. for Research on Aging, Novato, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  9. Chinese Academy of Sciences (CAS), Shanghai (China); Univ. of Washington, Seattle, WA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC); National Key Research and Development Program of China; National Natural Science Foundation of China (NNSFC)
OSTI Identifier:
1591837
Grant/Contract Number:  
AC02-05CH11231; 2016YFC1302400; 81472709; 31671425; 31871380; 81472228; 81201535; 81302065; 81472202
Resource Type:
Accepted Manuscript
Journal Name:
Aging Cell
Additional Journal Information:
Journal Volume: 18; Journal Issue: 6; Journal ID: ISSN 1474-9718
Publisher:
Anatomical Society - Wiley
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; aging; amphiregulin; cancer resistance; clinical biomarker; combinational treatment; programmed cell death 1 ligand; senescence-associated secretory phenotype; stroma

Citation Formats

Xu, Qixia, Long, Qilai, Zhu, Dexiang, Fu, Da, Zhang, Boyi, Han, Liu, Qian, Min, Guo, Jianming, Xu, Jianmin, Cao, Liu, Chin, Y. Eugene, Coppé, Jean‐Philippe, Lam, Eric W. ‐F., Campisi, Judith, and Sun, Yu. Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD-L1)-mediated immunosuppression. United States: N. p., 2019. Web. https://doi.org/10.1111/acel.13027.
Xu, Qixia, Long, Qilai, Zhu, Dexiang, Fu, Da, Zhang, Boyi, Han, Liu, Qian, Min, Guo, Jianming, Xu, Jianmin, Cao, Liu, Chin, Y. Eugene, Coppé, Jean‐Philippe, Lam, Eric W. ‐F., Campisi, Judith, & Sun, Yu. Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD-L1)-mediated immunosuppression. United States. https://doi.org/10.1111/acel.13027
Xu, Qixia, Long, Qilai, Zhu, Dexiang, Fu, Da, Zhang, Boyi, Han, Liu, Qian, Min, Guo, Jianming, Xu, Jianmin, Cao, Liu, Chin, Y. Eugene, Coppé, Jean‐Philippe, Lam, Eric W. ‐F., Campisi, Judith, and Sun, Yu. Sat . "Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD-L1)-mediated immunosuppression". United States. https://doi.org/10.1111/acel.13027. https://www.osti.gov/servlets/purl/1591837.
@article{osti_1591837,
title = {Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD-L1)-mediated immunosuppression},
author = {Xu, Qixia and Long, Qilai and Zhu, Dexiang and Fu, Da and Zhang, Boyi and Han, Liu and Qian, Min and Guo, Jianming and Xu, Jianmin and Cao, Liu and Chin, Y. Eugene and Coppé, Jean‐Philippe and Lam, Eric W. ‐F. and Campisi, Judith and Sun, Yu},
abstractNote = {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.},
doi = {10.1111/acel.13027},
journal = {Aging Cell},
number = 6,
volume = 18,
place = {United States},
year = {2019},
month = {9}
}

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