title: Intratumoral Immunization by p19Arf and Interferon-β Gene Transfer in a Heterotopic Mouse Model of Lung Carcinoma.
abstract: Therapeutic strategies that act by eliciting and enhancing antitumor immunity have been clinically validated as an effective treatment modality but may benefit from the induction of both cell death and immune activation as primary stimuli. Using our AdRGD-PG adenovector platform, we show here for the first time that in situ gene transfer of p19Arf and interferon-β (IFNβ) in the LLC1 mouse model of lung carcinoma acts as an immunotherapy. Although p19Arf is sufficient to induce cell death, only its pairing with IFNβ significantly induced markers of immunogenic cell death. In situ gene therapy with IFNβ, either alone or in combination with p19Arf, could retard tumor progression, but only the combined treatment was associated with a protective immune response. Specifically in the case of combined intratumoral gene transfer, we identified 167 differentially expressed genes when using microarray to evaluate tumors that were treated in vivo and confirmed the activation of CCL3, CXCL3, IL1α, IL1β, CD274, and OSM, involved in immune response and chemotaxis. Histologic evaluation revealed significant tumor infiltration by neutrophils, whereas functional depletion of granulocytes ablated the antitumor effect of our approach. The association of in situ gene therapy with cisplatin resulted in synergistic elimination of tumor progression. In all, in situ gene transfer with p19Arf and IFNβ acts as an immunotherapy involving recruitment of neutrophils, a desirable but previously untested outcome, and this approach may be allied with chemotherapy, thus providing significant antitumor activity and warranting further development for the treatment of lung carcinoma.
authors.affiliation: Viral Vector Laboratory, Center for Translational Investigation in Oncology, Cancer Institute of Sao Paulo/LIM 24, University of São Paulo School of Medicine, Brazil.
authors.forename: João Paulo Portela
authors.initials: JPP
authors.lastname: Catani
authors.affiliation: Viral Vector Laboratory, Center for Translational Investigation in Oncology, Cancer Institute of Sao Paulo/LIM 24, University of São Paulo School of Medicine, Brazil.
authors.forename: Ruan F V
authors.initials: RFV
authors.lastname: Medrano
authors.affiliation: Viral Vector Laboratory, Center for Translational Investigation in Oncology, Cancer Institute of Sao Paulo/LIM 24, University of São Paulo School of Medicine, Brazil.
authors.forename: Aline
authors.initials: A
authors.lastname: Hunger
authors.affiliation: Viral Vector Laboratory, Center for Translational Investigation in Oncology, Cancer Institute of Sao Paulo/LIM 24, University of São Paulo School of Medicine, Brazil.
authors.forename: Paulo
authors.initials: P
authors.lastname: Del Valle
authors.affiliation: Laboratory of Cell and Molecular Biology, Department of Immunology, Biomedical Sciences Institute, University of São Paulo, Brazil.
authors.forename: Sandy
authors.initials: S
authors.lastname: Adjemian
authors.affiliation: Viral Vector Laboratory, Center for Translational Investigation in Oncology, Cancer Institute of Sao Paulo/LIM 24, University of São Paulo School of Medicine, Brazil.
authors.forename: Daniela Bertolini
authors.initials: DB
authors.lastname: Zanatta
authors.affiliation: Equipe 11 Labellisée Ligue Contre le Cancer, Centre de Recherche des Cordeliers, Paris, France; U1138, INSERM, Paris, France; Université Paris Descartes, Sorbonne Paris Cité, Paris, France; Université Pierre et Marie Curie, Paris, France; Metabolomics and Cell Biology Platforms, Gustave Roussy Comprehensive Cancer Institute, Villejuif, France; Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France; Department of Women's and Children's Health, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Guido
authors.initials: G
authors.lastname: Kroemer
authors.affiliation: Gene Therapy Laboratory, Department of Cell and Developmental Biology, Biomedical Sciences Institute, University of São Paulo, Brazil.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Costanzi-Strauss
authors.affiliation: Viral Vector Laboratory, Center for Translational Investigation in Oncology, Cancer Institute of Sao Paulo/LIM 24, University of São Paulo School of Medicine, Brazil. Electronic address: bstrauss@usp.br.
authors.forename: Bryan E
authors.initials: BE
authors.lastname: Strauss