Interferon-alpha (IFN-alpha)-conditioned DC preferentially stimulate type-1 and limit Treg-type in vitro T-cell responses from RCC patients.

ABSTRACT

Dendritic cells (DCs) are potent antigen presenting cells and represent attractive candidates for use in novel immunotherapies for patients with renal cell carcinoma (RCC), a disease that has proven refractory to conventional treatment modalities, such as chemotherapy and radiotherapy. Given the perceived need to augment antitumor type-1 immunity (TC1 and Th1) as a therapeutic end point, and the known functional plasticity of DC populations that may display heterogeneous capacity to promote T-cell responses, we sought to identify a preferred DC preparation with this capacity. We compared 2 different preparations of monocyte-derived DC using interferon-alpha (IFN-alpha) (IFN-DC and alphaDC1) with classic DCs "matured" (mDCs) using interleukin-1beta/interleukin-6/tumor necrosis factor-alpha/prostaglandin E2, for their ability to promote autologous TC1 antitumor responses from RCC patients in vitro. IFN-alpha-conditioned DC promoted significantly higher numbers of RCC-specific CD8+ T cells exhibiting a cytotoxic phenotype after in vitro stimulation (IVS) than cytokine cocktail-mDCs. Furthermore, IVS using IFN-DCs was able to diminish regulatory-type T cells among CD4+ T-cell responder populations versus IVS using conventional mDC-based vaccines. These data emphasize an important role for IFN-alpha in modulating the immunologic functions of DCs toward a polarized DC1-type capable of coordinately promoting TH1-type and TC1-type T-cell mediated immunity and supports the translational development of patient-derived IFN-alpha-conditioned DC for use in novel immunotherapies for patients with RCC, and in whom, endogenous tumor-specific TC1 effector cells may be dysfunctional, anergic, or prone to undergo apoptosis.