title: Erlotinib inhibits T-cell-mediated immune response via down-regulation of the c-Raf/ERK cascade and Akt signaling pathway.
abstract: Erlotinib is a potent inhibitor of epidermal growth factor receptor tyrosine kinase and has been demonstrated to treat advanced or metastatic non-small cell lung cancer to prolong survival after failure of first-line or second-line chemotherapy. However, little is known about its effects on immune system. In the present study, we aimed to investigate the immunosuppressive activity of erlotinib on T lymphocytes both in vitro and in vivo, and further explore its potential molecular mechanism. Erlotinib exerted a significant inhibition on the T cell proliferation and activation induced by concanavalin A, anti-CD3 plus anti-CD28, staphylococcal enterotoxin B or phorbol myristate acetate respectively in a concentration-dependent manner and it also inhibited the secretion of the proinflammatory cytokines such as IL-2 and IFN-γ of activated T cells. Further study showed that erlotinib caused G0/G1 arrest and suppressed the phosphorylations of c-Raf, ERK and Akt in activated T cells. Moreover, erlotinib significantly ameliorated picryl chloride-induced ear contact dermatitis in a dose-dependent manner in vivo. In summary, these findings suggest that erlotinib may cause the impairment of T-cell-mediated immune response both in vitro and in vivo through inhibiting T cell proliferation and activation, which is closely associated with its potent down-regulation of the c-Raf/ERK cascade and Akt signaling pathway.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University 22 Han Kou Road, Nanjing 210093, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Luo
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gu
authors.forename: Wei
authors.initials: W
authors.lastname: Zheng
authors.forename: Xingxin
authors.initials: X
authors.lastname: Wu
authors.forename: Fangyuan
authors.initials: F
authors.lastname: Gong
authors.forename: Liyun
authors.initials: L
authors.lastname: Gu
authors.forename: Yang
authors.initials: Y
authors.lastname: Sun
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects* / Q000276:immunology; D000069347:Erlotinib Hydrochloride; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D005260:Female; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors* / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000633:toxicity*; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000633:toxicity*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D051058:Oncogene Protein v-akt; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases