Evaluación del efecto de Imiquimod sobre TAPCells y líneas de melanoma humanas como posible agente adyuvante en terapia contra el cáncer
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2016
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es
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Universidad Andrés Bello
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Licencia CC
Licencia CC
Resumen
El melanoma es un cáncer cuya incidencia y mortalidad han aumento significativamente en las últimas dos décadas. Hoy en día, terapias basadas en la manipulación del sistema inmune ha demostrado resultados alentadores en esta patología, como por ejemplo, el uso vacunas de células dendríticas (DCs).
En nuestro laboratorio hemos inmunizado a más de 300 pacientes con melanoma avanzado utilizando DCs cargadas con lisados de melanoma alogénicos, denominadas TAPCells. Hemos observado dos grupos de pacientes, uno que genera respuestas de hipersensibilidad retardada (DTH) contra antígenos tumorales, lo que indica el desarrollo de memoria inmunológica in vivo, denominados respondedores (DTH+) y otro que no genera memoria y que denominamos no respondedores (DTH-). Clínicamente, aquellos respondedores mostraron una sobrevida tres veces superior al grupo no respondedor.
En la actualidad, se ha demostrado que el uso de agonistas de TLR-7 como adyuvantes en vacunas antitumorales favorecen la generación de respuestas de tipo TH1 en modelos tumorales murinos. En este proyecto evaluamos la utilización de Imiquimod, un agonista TLR-7 como adyuvante en la maduración de TAPCells. Esto conllevó un aumento en la expresión de la molécula co-estimuladora CD86, con disminución de PD-L1, generando así una disminución de la relación PDL1/CD86 lo que se traduce en una mayor capacidad de activación por las DCs sobre los linfocitos. Es más, las TAPCells tratadas con Imiquimod fueron capaces de aumentar la población CD4+ productora de IFN-. Adicionalmente, Imiquimod tuvo un efecto directo sobre líneas de melanoma humano, no sólo en generar un aumento de MHC-I y MICA/B, sino también de incrementar, la citotoxicidad mediada por linfocitos T CD8+ Mart-1 específicos y células NK. De esta forma, presentamos los primeros estudios para modificar la terapia TAPCells al ocupar un agonista TLR7. Además, demostramos un nuevo rol de Imiquimod sobre células tumorales de melanoma que podría indicar una alternativa para el manejo de tumores localizados.
Malingant Melanoma incidence and mortality have increased through the last decades. Nowadays, therapies that modulate the immune system have proven to be succesfull to treat this pathology, such as dendritic cells (DCs) based immunotherapies. In our laboratory we have immunized more than 300 patients with advanced melanoma using DCs loaded with allogeneic melanoma lysates, called TAPCells. We observed two groups of patients, one that generates delayed hypersensitivity responses (DTH) against tumor antigens, indicating the development of immunological memory in vivo, called responders (DTH +) and one that does not generate memory and call non responders (DTH -). Clinically, those responders showed a survival rate three times higher than non-responder group. At present, it has been shown that the use of TLR-7 agonists as adjuvants in tumor vaccines substantially favor the generation of TH1-type responses in murine tumor models. This project evaluated the use of Imiquimod a TLR-7 agonist as an adjuvant in the maturation of TAPCells. This entailed an increase in the expression of the costimulatory molecule CD86, with decreased PD- L1, thus generating a lower ratio PD- L1 / CD86 resulting in increased activation ability DCs on lymphocytes. Moreover, TAPCells treated with Imiquimod were able to increase the population of CD4 + IFN- production. Additionally, Imiquimod had a direct effect on human melanoma lines, not only in generating an increase in MHC- I, MICA/B among, other molecules examined, but also to increase the cytotoxicity mediated by specific CD8+ Mart-1 lymphocytes and NK cells. Thus, we present the first preclinical modifications to the TAPCells therapy. Furthermore, we demonstrate a new role of Imiquimod on melanoma tumor cells that might indicate an alternative for the management of localized tumors.
Malingant Melanoma incidence and mortality have increased through the last decades. Nowadays, therapies that modulate the immune system have proven to be succesfull to treat this pathology, such as dendritic cells (DCs) based immunotherapies. In our laboratory we have immunized more than 300 patients with advanced melanoma using DCs loaded with allogeneic melanoma lysates, called TAPCells. We observed two groups of patients, one that generates delayed hypersensitivity responses (DTH) against tumor antigens, indicating the development of immunological memory in vivo, called responders (DTH +) and one that does not generate memory and call non responders (DTH -). Clinically, those responders showed a survival rate three times higher than non-responder group. At present, it has been shown that the use of TLR-7 agonists as adjuvants in tumor vaccines substantially favor the generation of TH1-type responses in murine tumor models. This project evaluated the use of Imiquimod a TLR-7 agonist as an adjuvant in the maturation of TAPCells. This entailed an increase in the expression of the costimulatory molecule CD86, with decreased PD- L1, thus generating a lower ratio PD- L1 / CD86 resulting in increased activation ability DCs on lymphocytes. Moreover, TAPCells treated with Imiquimod were able to increase the population of CD4 + IFN- production. Additionally, Imiquimod had a direct effect on human melanoma lines, not only in generating an increase in MHC- I, MICA/B among, other molecules examined, but also to increase the cytotoxicity mediated by specific CD8+ Mart-1 lymphocytes and NK cells. Thus, we present the first preclinical modifications to the TAPCells therapy. Furthermore, we demonstrate a new role of Imiquimod on melanoma tumor cells that might indicate an alternative for the management of localized tumors.
Notas
Tesis (Magíster en Biotecnología)
Palabras clave
Cáncer de Piel, Terapia, Medicamentos, Uso Terapéutico, Melanoma