RESUMEN
Topical application of small molecule Toll-like receptor 7 (TLR7) agonists is highly effective for the treatment of skin tumors, whereas their systemic application has been largely unsuccessful for cancer therapy. One reason may be that repeated systemic application of TLR ligands can induce a state of immune unresponsiveness, termed TLR tolerance. We show here that a single injection of the TLR7 agonist R848 in mice induces a short period of increased response to TLR stimulation followed by a state of hyporesponsiveness lasting several days. This state is characterized by inhibited secretion of the key cytokines interleukin (IL)-12p70 and IL-6 as well as by a block in IFN-α production. We show for the first time that at the cellular level, TLR7 tolerance occurs in both plasmacytoid and myeloid dendritic cells, two cell populations that play a critical role in the initiation and amplification of antitumor immune responses. We further show that TLR7 tolerance in plasmacytoid dendritic cells is accompanied by downregulation of the adaptor protein IL-1 receptor-associated kinase 1. On the basis of these findings, we have designed a novel strategy for the treatment of tumors by using cycles of repeated R848 injections separated by treatment-free intervals. We show in CT26 tumor-bearing mice that this protocol circumvents TLR7 tolerance and improves the efficacy of cancer immunotherapy.
Asunto(s)
Carcinoma/tratamiento farmacológico , Neoplasias del Colon/tratamiento farmacológico , Imidazoles/uso terapéutico , Tolerancia Inmunológica/efectos de los fármacos , Glicoproteínas de Membrana/agonistas , Receptor Toll-Like 7/agonistas , Escape del Tumor/efectos de los fármacos , Animales , Carcinoma/inmunología , Células Cultivadas/inmunología , Neoplasias del Colon/inmunología , Citocinas/metabolismo , Células Dendríticas/metabolismo , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Interferón-alfa/farmacología , Quinasas Asociadas a Receptores de Interleucina-1/biosíntesis , Quinasas Asociadas a Receptores de Interleucina-1/genética , Interleucina-12/biosíntesis , Interleucina-12/genética , Interleucina-6/biosíntesis , Interleucina-6/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLAsunto(s)
Corticoesteroides/uso terapéutico , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Linfoma de Células T/tratamiento farmacológico , Paniculitis/tratamiento farmacológico , Resultado Fatal , Humanos , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/patología , Linfoma de Células T/complicaciones , Linfoma de Células T/patología , Paniculitis/complicaciones , Paniculitis/patología , RecurrenciaAsunto(s)
Células Dendríticas/patología , Leucemia Mieloide/patología , Enfermedad Aguda , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígenos CD4/análisis , Antígeno CD56/análisis , Células Dendríticas/metabolismo , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Leucemia Mieloide/tratamiento farmacológico , Masculino , Inducción de Remisión , Factores de Tiempo , Resultado del TratamientoRESUMEN
Single-stranded RNA oligonucleotides containing an immunostimulatory motif (immunostimulatory RNA [isRNA]) are potent inducers of interferon-alpha via the Toll-like receptor 7. We investigated the effect of isRNA on the development of an immune response. We show that isRNA activates dendritic cells and induces production of Th1-type cytokines both in vitro and in vivo. Cytokine production led to bystander activation of T and B cells. We further demonstrate that isRNA triggers the generation of antigen-specific cytotoxic T cells and of an IgG2a-biased antibody response to antigen in a sequence-dependent manner. In summary, we provide evidence for the first time that isRNA oligonucleotides can simultaneously activate the innate and adaptive arms of the immune system.