ARTÍCULO

Strict requirement for vector-induced type I interferon in efficacious antitumor responses to virally encoded IL-12

Autores: Melero Bermejo, Ignacio; Quetglas Más, José Ignacio; Reboredo Prol, María de las Mercedes; Dubrot Armendáriz, Juan; Rodríguez Madoz, Juan Roberto; Mancheño, U.; Casales Zoco, Erkuden; Riezu Boj, José Ignacio; Ruiz Guillén, Marta; Ochoa Nieto, Maria del Carmen; Fernández de Sanmamed Gutiérrez, Miguel; Thieblemont, N.; Smerdou Picazo, Cristian; Hervas Stubbs, Sandra
Título de la revista: CANCER RESEARCH
ISSN: 0008-5472
Volumen: 75
Número: 3
Páginas: 497 - 507
Fecha de publicación: 2014
Resumen:
Host responses are increasingly considered important for the efficacious response to experimental cancer therapies that employ viral vectors, but little is known about the specific nature of host responses required. In this study, we investigated the role of host type I interferons (IFN-I) in the efficacy of virally delivered therapeutic genes. Specifically, we used a Semliki Forest virus encoding IL12 (SFV-IL12) based on its promise as an RNA viral vector for cancer treatment. Intratumoral injection of SFV-IL12 induced production of IFN-I as detected in serum. IFN-I production was abolished in mice deficient for the IFN beta transcriptional regulator IPS-1 and partially attenuated in mice deficient for the IFN beta signaling protein TRIF. Use of bone marrow chimeric hosts established that both hematopoietic and stromal cells were involved in IFN-I production. Macrophages, plasmacytoid, and conventional dendritic cells were each implicated based on cell depletion experiments. Further, mice deficient in the IFN-I receptor (IFNAR) abolished the therapeutic activity of SFV-IL12, as did a specific antibody-mediated blockade of IFNAR signaling. Reduced efficacy was not caused by an impairment in IL12 expression, because IFNAR-deficient mice expressed the viral IL12 transgene even more strongly than wild-type (WT) hosts. Chimeric host analysis for the IFNAR involvement established a strict requirement in hematopoietic cells. Notably, although tumor-specific CD8 T lymphocytes expand