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.

Introduction

Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor which plays an essential role in normal cell growth and differentiation, and is involved in tumor proliferation and survival. EGFR over-expression is a common feature in many human solid malignancies including non-small-cell lung cancer, and is associated with poor clinical prognosis (Onn et al., 2004, Gridelli et al., 2007). Erlotinib (Tarceva) is an oral available, selective, reversible inhibitor of EGFR tyrosine kinase (Akita and Sliwkowski, 2003, Perez-Soler, 2004). In vitro and in vivo studies show that erlotinib has activity against human colorectal, head and neck, non-small cell lung, and pancreatic tumor cells (Akita and Sliwkowski, 2003). The antitumor activity of erlotinib as a single agent and in combination with other targeted agents has been demonstrated in Phase II trials in many tumor types (Tang et al., 2006). Erlotinib has an established role in the treatment of locally advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen (Comis, 2005, Wong et al., 2009). In a Phase III trial, the addition of erlotinib to gemcitabine improves survival in advanced pancreatic cancer (Tang et al., 2006, Bareschino et al., 2007). Encouraging indications of antitumor activity are also reported in several phase II studies including monotherapy use of erlotinib in advanced head and neck cancer, colorectal, hepatocellular, biliary, gastroesophageal, and ovarian cancer (Bareschino et al., 2007, Ciardiello and Tortora, 2008). The adverse effect of erlotinib is reported to be immune-mediated toxicity (Li et al., 2010) including drug-induced hepatitis (Liu et al., 2007b, Saif, 2008, Pellegrinotti et al., 2009), interstitial lung disease (Liu et al., 2007a, Makris et al., 2007), Stevens-Johnson syndrome and toxic epidermal necrolysis (Chou et al., 2006, Lubbe et al., 2008, Bovenschen and Alkemade, 2009), but the mechanism of toxicity has not been elucidated.

Erlotinib is ~ 60% absorbed after oral administration and the maximal tolerated dose on a protracted daily schedule is 150 mg/daily (Bareschino et al., 2007, Gridelli et al., 2007). Although the pharmacodynamics and pharmacokinetics of erlotinib in both healthy volunteers and adult patients with cancer have been well-characterized (Hidalgo and Bloedow, 2003, Ling et al., 2006), little is known about the effect of erlotinib on immune system. The aim of this study is to investigate whether erlotinib affects T-cell-mediated immune response. Here we showed that erlotinib inhibited T-cell-mediated immune response in vivo and in vitro, which demonstrated its immunosuppressive activity was proved to be associated with its inhibition of c-Raf/ERK cascade and Akt signaling in T cells.