PMID- 31493351 OWN - NLM STAT- MEDLINE DCOM- 20200914 LR - 20240421 IS - 1474-9726 (Electronic) IS - 1474-9718 (Print) IS - 1474-9718 (Linking) VI - 18 IP - 6 DP - 2019 Dec TI - Targeting amphiregulin (AREG) derived from senescent stromal cells diminishes cancer resistance and averts programmed cell death 1 ligand (PD-L1)-mediated immunosuppression. PG - e13027 LID - 10.1111/acel.13027 [doi] LID - e13027 AB - 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. CI - (c) 2019 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd. FAU - Xu, Qixia AU - Xu Q AD - Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. FAU - Long, Qilai AU - Long Q AD - Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China. FAU - Zhu, Dexiang AU - Zhu D AD - Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. FAU - Fu, Da AU - Fu D AD - Central Laboratory for Medical Research, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China. FAU - Zhang, Boyi AU - Zhang B AD - CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. FAU - Han, Liu AU - Han L AD - CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. FAU - Qian, Min AU - Qian M AD - CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. FAU - Guo, Jianming AU - Guo J AD - Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China. FAU - Xu, Jianmin AU - Xu J AD - Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. FAU - Cao, Liu AU - Cao L AD - Key Laboratory of Medical Cell Biology, China Medical University, Shenyang, China. FAU - Chin, Y Eugene AU - Chin YE AD - Institute of Biology and Medical Sciences, Soochow University Medical College, Suzhou, Jiangsu, China. FAU - Coppe, Jean-Philippe AU - Coppe JP AD - Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, CA, USA. FAU - Lam, Eric W-F AU - Lam EW AD - Department of Surgery and Cancer, Imperial College London, London, UK. FAU - Campisi, Judith AU - Campisi J AD - Buck Institute for Research on Aging, Novato, CA, USA. AD - Lawrence Berkeley National Laboratory, Life Sciences Division, Berkeley, CA, USA. FAU - Sun, Yu AU - Sun Y AUID- ORCID: 0000-0001-7121-9112 AD - Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. AD - CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. AD - Department of Medicine and VAPSHCS, University of Washington, Seattle, WA, USA. LA - eng GR - UL1 TR000005/TR/NCATS NIH HHS/United States GR - 2012MayPR070/BBC_/Breast Cancer Now/United Kingdom GR - A12011/CRUK_/Cancer Research UK/United Kingdom GR - 2012NOVPHD016/BCN_/Breast Cancer Now/United Kingdom GR - 2012MAYPR070/BCN_/Breast Cancer Now/United Kingdom GR - TR000005/GF/NIH HHS/United States GR - 12011/CRUK_/Cancer Research UK/United Kingdom GR - 2012NovPhD016/BBC_/Breast Cancer Now/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. DEP - 20190907 PL - England TA - Aging Cell JT - Aging cell JID - 101130839 RN - 0 (Amphiregulin) RN - 0 (Antineoplastic Agents) RN - 0 (B7-H1 Antigen) RN - 0 (CD274 protein, human) SB - IM MH - Amphiregulin/genetics/*immunology MH - Animals MH - Antineoplastic Agents/pharmacology MH - B7-H1 Antigen/antagonists & inhibitors/genetics/*immunology MH - Cells, Cultured MH - Cellular Senescence/drug effects/*immunology MH - Drug Resistance, Neoplasm/drug effects MH - Humans MH - Mice MH - Mice, Inbred NOD MH - Mice, SCID MH - Stromal Cells/drug effects/*immunology MH - Tumor Microenvironment/drug effects PMC - PMC6826133 OTO - NOTNLM OT - aging OT - amphiregulin OT - cancer resistance OT - clinical biomarker OT - combinational treatment OT - programmed cell death 1 ligand OT - senescence-associated secretory phenotype OT - stroma COIS- The authors declare that there is no conflict of interest. EDAT- 2019/09/08 06:00 MHDA- 2020/09/15 06:00 PMCR- 2019/12/01 CRDT- 2019/09/08 06:00 PHST- 2019/05/12 00:00 [received] PHST- 2019/07/29 00:00 [revised] PHST- 2019/08/04 00:00 [accepted] PHST- 2019/09/08 06:00 [pubmed] PHST- 2020/09/15 06:00 [medline] PHST- 2019/09/08 06:00 [entrez] PHST- 2019/12/01 00:00 [pmc-release] AID - ACEL13027 [pii] AID - 10.1111/acel.13027 [doi] PST - ppublish SO - Aging Cell. 2019 Dec;18(6):e13027. doi: 10.1111/acel.13027. Epub 2019 Sep 7.