RESUMEN
Immune-cell-based approaches using cytotoxic and dendritic cells are under constant scrutiny to design novel therapies for the treatment of tumors. These strategies are hampered by the lack of efficient and economical large-scale production methods for effector cells. Here we describe the propagation of large amounts of a unique population of CD4(+) cytotoxic T cells, which we termed tumor killer T cells (TKTC), because of their potent and broad antitumor cell activity. With this cultivation strategy, TKTCs from peripheral blood mononuclear cells are generated within a short period of time using a pulse with a stimulating cell line followed by continuous growth in serum-free medium supplemented with a mixture of interleukin-2 and cyclosporin A. Expression and functional profiling did not allow a classification of TKTCs to any thus far defined subtype of T cells. Cytotoxic assays showed that TKTCs kill a panel of tumor targets of diverse tissue origin while leaving normal cells unaffected. Blocking experiments revealed that TKTC killing was, to a significant extent, mediated by tumor necrosis factor-related apoptosis-inducing ligand and was independent of MHC restriction. These results suggest that TKTCs have a high potential as a novel tool in the adoptive immunotherapy of cancer.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Inmunoterapia Adoptiva/métodos , Linfocitos T Citotóxicos/inmunología , Animales , Apoptosis/inmunología , Antígenos CD4/inmunología , Línea Celular Tumoral , Neoplasias Colorrectales/inmunología , Citocinas/biosíntesis , Citocinas/inmunología , Citotoxicidad Inmunológica/inmunología , Factores de Transcripción Forkhead/biosíntesis , Factores de Transcripción Forkhead/genética , Humanos , Masculino , Ratones , Neoplasias de la Próstata/inmunología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Receptores de Antígenos de Linfocitos T alfa-beta/biosíntesis , Receptores de Antígenos de Linfocitos T alfa-beta/inmunologíaRESUMEN
Originally identified as antiviral substances produced by infected cells, type I interferons (IFN-I) are now known to have a wide range of additional activities within both the innate and adaptive immune response. Here we review properties of IFN-I contributing to their 'natural immune adjuvant' character, and their important role for the function of complete Freund's adjuvant (CFA) and the TLR9-dependent immune adjuvant IC31. We show data to demonstrate that treatment with IFN-I boosts the ability of vaccine/adjuvant combinations to induce peptide-specific CTL in both young and old mice. We view these findings in the perspective of previous clinical applications of IFN-I for vaccination.