Targeting AREG derived from senescent stromal cells diminishes cancer resistance and averts PD-L1-mediated immunosuppression

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Title: Targeting AREG derived from senescent stromal cells diminishes cancer resistance and averts PD-L1-mediated immunosuppression
Authors: Xu, Q
Long, Q
Zhu, D
Fu, D
Zhang, B
Han, L
Qian, M
Guo, J
Xu, J
Cao, L
Chin, E
Coppe, JP
Lam, E
Campisi, J
Sun, Y
Item Type: Journal Article
Abstract: Agingis characterized by a progressive loss of physiological integrity, while cancer represents one of the primarypathologicalfactorsthat severely threatenhuman lifespan and healthspan.In clinical oncology, drug resistance limits the efficacy of most anticancer treatments, andidentification of major mechanisms remains a key to solve thischallenging 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), aprocess that remarkably enhances cancer malignancy including acquired resistance mediated by EGFR. Furthermore, Paracrine AREG induces PD-L1 expression in recipient cancer cells and createsan immunosuppressive TME via immune checkpoint activation against cytotoxic lymphocytes. Targeting AREG not only minimizedchemoresistanceof cancer cells, but also restored immunocompetency when combined with classical chemotherapy in humanized animals. Our study underscores the potential of in vivoSASP 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.
Date of Acceptance: 4-Aug-2019
URI: http://hdl.handle.net/10044/1/72754
ISSN: 1474-9726
Publisher: Wiley Open Access
Journal / Book Title: Aging Cell
Copyright Statement: This paper is embargoed until publication. Once published it will be available fully open access.
Sponsor/Funder: Cancer Research UK
Breast Cancer Care & Breast Cancer Now
Medical Research Council (MRC)
Funder's Grant Number: 12011
2012MayPR070
MR/N012097/1
Keywords: 11 Medical and Health Sciences
06 Biological Sciences
Developmental Biology
Publication Status: Accepted
Embargo Date: publication subject to indefinite embargo
Appears in Collections:Division of Surgery
Division of Cancer



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