title: Dexamethasone enhances programmed cell death 1 (PD-1) expression during T cell activation: an insight into the optimum application of glucocorticoids in anti-cancer therapy.
abstract: BACKGROUND
  Programmed cell death 1 (PD-1) is a key cell-surface receptor of CD28 superfamily that triggers inhibitory pathways to attenuate T-cell responses and promote T-cell tolerance. As a crucial role in tumor immunity, PD-1 has been a focus of studies in anti-cancer therapy. It has been approved that tumors could exploit PD-1-dependent immune suppression for immune evasion. Considering the wide use of glucocorticoids (GCs) in anti-cancer therapy and their immunosuppressive effects, we explored whether GCs could influence the expression of PD-1.
  
  
  RESULTS
  In our study, we used dexamethasone (DEX) as a model glucocorticoid and demonstrated that DEX could enhance PD-1 expression in a dose-dependent manner. The effects were completely inhibited by the glucocorticoid receptor (GR) antagonist mifepristone (RU486), indicating that the effect of DEX on PD-1 is mediated through GR. We further found the sensitivity to DEX-induced upregulation of PD-1 expression had a significant difference between different T cell subsets, with memory T cells more susceptible to this effect. We also showed that DEX could suppress T cell functions via inhibition of cytokines production such as IL-2, IFN-γ, TNF-α and induction of apoptosis of T cells.
  
  
  CONCLUSIONS
  Our findings suggest a novel way by which DEX suppress the function of activated T lymphocytes by enhancing expression of PD-1 and provide an insight into the optimum clinical application of GCs.
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China. fdxkl2013@163.com.|Department of Oncology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai, 200032, China. fdxkl2013@163.com.
authors.forename: Kailin
authors.initials: K
authors.lastname: Xing
authors.affiliation: Department of Oncology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai, 200032, China. 13211230001@fudan.edu.cn.|Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China. 13211230001@fudan.edu.cn.
authors.forename: Bingxin
authors.initials: B
authors.lastname: Gu
authors.affiliation: Cancer Research Institute of Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China. pingzhang0503@yahoo.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Medical Oncology, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, China. xhwu2015@yahoo.com.|Department of Oncology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai, 200032, China. xhwu2015@yahoo.com.
authors.forename: Xianghua
authors.initials: X
authors.lastname: Wu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000494:pharmacology; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects*; D008807:Mice, Inbred BALB C; D015735:Mifepristone / Q000494:pharmacology; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D005938:Glucocorticoids; C105992:PDCD1 protein, human; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D012333:RNA, Messenger; D015735:Mifepristone; D003907:Dexamethasone; D006854:Hydrocortisone