Reduction of circulating regulatory T cells by intravenous high-dose interferon alfa-2b treatment in melanoma patients

Abstract

High-dose interferon alfa-2b (IFNα-2b) is the only approved adjuvant systemic therapy for resected, high risk melanoma in the United States (Fecher and Flaherty, in Natl Compr Cancer Netw 7:295-304, 2009). Recently, two important meta-analyses of randomized trials (Wheatley et al., in J Clin Oncol, 2007; Mocellin et al. in J Natl Cancer Inst, 2010) investigating IFNα-2b versus observation in high risk melanoma patients, showed that adjuvant IFNα-2b has an impact both on relapse-free survival (RFS) and overall survival (OS) independently by dosage, duration and route compared with observation in high risk melanoma patients. Despite of an absolute benefits of 3 % (Wheatley et al., in J Clin Oncol, 2007), this treatment is associated with significant toxicity, which impacts on patient quality of life. A better understanding of the mechanism of action may help to potentiate the clinical efficacy and reduce the toxicity of IFNα-2b/Peg-IFNα-2b. Numerous studies suggest that interferon's mechanism of action in melanoma is primarily immunomodulatory (Table 1) (de La Salmoniere, in Clin Cancer Res 6:4713-4718, 2000; Stuckert, in J Clin Oncol 25:8506, 2007; Gogas et al., in N Engl J Med 354:709-718, 2006; Moschos et al., in J Clin Oncol 24:3164-3171, 2006; Ascierto and Kirkwood, in J Transl Med 6:62, 2008) Recent efforts to elucidate the mechanism of action for interferon have focused upon signal transducers and activators of transcription (STAT) (Simons et al., in J Transl Med 9:52, 2011) signaling and immunoregulatory responses mediated by regulatory T cells (Tregs) (Wang et al., in Clin Cancer Res 13:1523-1531, 2007; Clin Cancer Res 14:8314-8320, 2008). Tregs are a suppressive CD4+ T cell population that is present, along with primed effector T cells, in tumor and tumor-draining lymph nodes (Hiura et al. in J Immunol 175:5058-5066, 2005). Tregs express high levels of surface antigens such as CD25, cytotoxic T lymphocyte associated antigen 4 (CTLA-4), and glucocorticoid-induced tumor necrosis factor receptor (GITR) (Takahashi et al., in J Exp Med 192:303-310, 2000; Shimizu et al., in Nat Immunol 3:135-142, 2002). Moreover, Tregs express a characteristic nuclear transcription regulator, forkhead box P3 (FoxP3) (Hori et al., in Science 299:1057-1061, 2003; Gabriel and Lattime, in Clin Cancer Res 13:785-788, 2007). The presence of Tregs in tumor-draining lymph nodes and tumors provides a potential inhibitory population that may block or balance effector cell function. Thus, depletion of Tregs or blockade of Treg function using targeted antibodies or other strategies might be able to remove Treg suppression and enhance antitumor immunity (Viguier et al., in J Immunol 173:1444-1453, 2004). We conducted an observational study to examine whether the induction phase of the FDA-approved HDI regimen administered iv in patients with stage 3-4 melanoma (20 MU/m(2) intravenously (IV) five times per week for 4 weeks) reduced the number of Treg cells in the peripheral blood.