Type 2 Bias of T Cells Expanded from the Blood of Melanoma Patients Switched to Type 1 byIL-12p70mRNA–Transfected Dendritic Cells

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Abstract
Melanoma patients may exhibit a TH2-skewed cytokine profile within blood and tumor-infiltrating lymphocytes. Therapies that induce beneficial TH1-type tumor-specific immune responses, therefore, are highly desirable. Dendritic cells (DC) are widely used as immune adjuvants for cancer. Before their administration, DC are generally induced to mature with a cocktail of recombinant cytokines [interleukin (IL)-1β, tumor necrosis factor α, and IL-6] and prostaglandin E2 (PGE2), which is added to preserve the ability of DC to migrate to draining lymph nodes. However, PGE2 suppresses the production of IL-12p70, a cytokine essential for differentiation of TH1 responses. In this study, human DC were transfected with IL-12p70 mRNA and tested for their ability to alter the TH2 type bias manifested by blood T cells of patients with melanoma. Transfected DC secreted high levels of bioactive IL-12p70, as indicated by their capacity to enhance natural killer cell activity, skew TH1 responses in allogeneic mixed lymphocyte reactions through reduction of IL-4 and IL-5, and prime CD8+ T cells to the melanoma-associated antigen Melan A/MART-1. Furthermore, T-cell lines primed in vitro from the blood of melanoma patients showed strong type 2 skewing that was dramatically reversed by IL-12p70 transfection of autologous DC. Thus, IL-12p70 transfection of clinical DC preparations may enhance type 1 antitumor responses and may thereby contribute to effective immune-based therapy. [Cancer Res 2008;68(22):9441–50]