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IRB (Institute for Research in Biomedicine)

IRB (Institute for Research in Biomedicine)

El IRB Barcelona es un centro de investigación de primer nivel dedicado a estudiar cuestiones fundamentales de la salud y las enfermedades humanas. El IRB Barcelona fue fundado en octubre de 2005 por la Generalitat de Catalunya y la Universidad de Barcelona, y está situado en el Parque Científico de Barcelona. C/ Baldiri Reixac 10. 08028 Barcelona. http://www.irbbarcelona.org

El IRB Barcelona abre la puerta a usar la inmunoterapia para tratar tumores de colon agresivos y sus metástasis

Fuente: IRB | Publicado: 20-02-2018
Un equipo liderado por el investigador ICREA Eduard Batlle descubre la eficacia de los tratamientos basados en potenciar el sistema inmunitario contra el cáncer de colon si se combinan con un neutralizador de la proteína TGF-beta.
Los investigadores desarrollan un modelo de ratón que mimetiza el cáncer de colon avanzado humano, lo que ha permitido estudiar el comportamiento del sistema inmunitario por primera vez.
Derechos: La imagen muestra un tumor metastásico de colon infiltrado por el sistema inmune (en marrón) tras la combinación del inhibidor de TGF-beta e inmunoterapia (Autor: Daniele Tauriello, IRB Barcelona)
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La inmunoterapia, es decir terapias basadas en activar el sistema inmunitario contra las células cancerígenas, se ha convertido en poco tiempo en un arma muy eficaz para tratar algunos tumores como el melanoma o el cáncer de pulmón. Sin embargo, hasta ahora, la mayoría de los tumores del colon parecían insensibles a este tipo de terapias y, por tanto, se había postulado que este tipo de tumor simplemente es invisible para el sistema inmunitario. Un equipo liderado por el investigador ICREA, Eduard Batlle, en el Instituto de Investigación Biomédica (IRB Barcelona) explica en un trabajo publicado en la revista Nature que la hormona TGF-beta es la responsable de que el sistema inmunitario sea ciego ante las células tumorales de colon.



“Los pocos ensayos clínicos de inmunoterapia con pacientes portadores del subtipo de cáncer de colon más frecuente no estaban dando buenos resultados y no se comprendía bien por qué” explica Eduard Batlle, líder del estudio.


Neutralizando la acción del TGF-beta, las células del sistema inmunitario consiguen infiltrar y reconocer el tumor, combatir el cáncer e incluso prevenir la aparición de las metástasis generadas en hígado y pulmón por tumores que se desarrollan en colon en un modelo preclínico de ratón que mimetiza la enfermedad en humanos. Además, y más importante, demuestran que combinando el inhibidor de TGF-beta con inmunoterapias ya disponibles, el efecto anti-tumoral se potencia y el sistema inmune elimina de forma eficaz las metástasis ya establecidas, que de otra forma matarían al individuo en pocas semanas.


Modelo mimético del cáncer de colon agresivo de humanos


El científico Daniele Tauriello, investigador postdoctoral y primer autor del artículo, aplicó a ratones de laboratorio cuatro de las mutaciones genéticas más comunes presentes en los tumores humanos de colon avanzados. “La creación del modelo animal nos llevó cuatro años pero dimos en el clavo”, relata el investigador.



Tras comprobar la similitud con los tumores humanos agresivos, crearon un biobanco de organoides tumorales -minitumores en tres dimensiones-, para poder re-introducirlos de forma controlada en ratones inmunocompetentes. “Para estudiar el sistema inmunitario el tumor debe ser de ratón, de otro modo su organismo lo rechazaría”, explica. A través de este modelo que mimetiza las principales características del cáncer de colon metastásico desarrollado en pacientes, pudieron estudiar cómo las células cancerígenas conseguían ocultarse de la acción del sistema inmunitario.


Más allá del cáncer de colon


Alrededor del 40-50% de los pacientes con un tumor en el colon recaerán en la enfermedad en forma de metástasis, con tumores que se reproducirán en el hígado o pulmón principalmente. “Cuando hay un diagnóstico de cáncer de colon en los estadios más avanzados, los oncólogos no tienen a su disposición tratamientos eficaces que puedan curar al paciente”, explica Eduard Batlle.


Este trabajo abre la puerta a que se desarrolle el primer tratamiento basado en inmunoterapia para pacientes con cáncer de colon metastásico, y para aquellos pacientes con mal pronóstico, pero que todavía no han desarrollado metástasis.



“Oncólogos y farmacéuticas iniciarán pronto ensayos clínicos que combinen inhibidores de TGF-beta, ya disponibles para uso clínico, con inmunoterapias. Estamos convencidos de que muchos pacientes de cáncer colorrectal se beneficiaran de esta estrategia terapéutica”, señalan.


Nature publica en el mismo número otro estudio de la farmacéutica norteamericana Genentech que llega a las mismas conclusiones que el equipo de Batlle investigando la falta de respuesta a la inmunoterapia en pacientes con cáncer de vejiga. “Este segundo trabajo demuestra que el descubrimiento va más allá del cáncer de colon. Aparentemente múltiples tipos de tumores utilizan la misma estrategia - la elevación de los niveles de TGF-beta en el entorno - para volverse invisibles al sistema inmunitario. Éstos también podrían beneficiarse de las inmunoterapias basadas en inhibir la acción de esta hormona”, opinan los científicos del IRB Barcelona.


El estudio ha contado con la colaboración del laboratorio de química liderado por Antoni Riera en el IRB Barcelona, que ha sintetizado el medicamento que neutraliza la acción de TGF-beta, y del trabajo de Toni Berenguer y Camille Stephan-Otto al frente de la plataforma de bioinformática y bioestadística, que han validado la similitud entre los tumores humanos y de ratones. Además el estudio ha contado con la colaboración del Departamento de Oncología y Patología del Hospital del Mar de Barcelona.


El trabajo se ha llevado a cabo con ayudas de la Fundación BBVA, Fundación Olga Torres (FOT), la Fundación Josef Steiner, el Consejo Europeo de Investigación (ERC en sus siglas en inglés) el Ministerio de Economía y Competitividad a través de fondos FEDER y con el apoyo de la Fundación Botín y de Banco Santander a través de su División Global Santander Universidades. Eduard Batlle y Daniele Tauriello son además miembros de la red CIBERONC, Centro de Investigación Biomédica en Red de Cáncer, de la que el laboratorio recibe fondos para desarrollar sus estudios.


Artículo de referencia: Daniele VF Tauriello, Sergio Palomo-Ponce, Diana Stork, Antonio Berenguer-Llergo, Jordi Badia-Ramentol, Mar Iglesias, Marta Sevillano, Sales Ibiza, Adria Cañellas, Xavier Hernando-Momblona, Daniel Byrom, Joan A Matarin, Alexandre Calon, Elisa I Rivas, Angel R Nebreda, Antoni Riera , Camille Stephan-Otto Attolini and Eduard Batlle TGF-beta drives immune evasion in genetically reconstituted colon cancer metastasis Nature (2018). DOI: http://dx.doi.org/10.1038/nature25492
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