TY - JOUR
T1 - Intratumoral immunization by p19arf and interferon-β gene transfer in a heterotopic mouse model of lung carcinoma
AU - Catani, João Paulo Portela
AU - Medrano, Ruan F.V.
AU - Hunger, Aline
AU - Valle, Paulo Del
AU - Adjemian, Sandy
AU - Zanatta, Daniela Bertolini
AU - Kroemer, Guido
AU - Costanzi-Strauss, Eugenia
AU - Strauss, Bryan E.
N1 - Publisher Copyright:
© 2016 The Authors.
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85000893462&partnerID=8YFLogxK
U2 - 10.1016/j.tranon.2016.09.011
DO - 10.1016/j.tranon.2016.09.011
M3 - Article
AN - SCOPUS:85000893462
SN - 1936-5233
VL - 9
SP - 565
EP - 574
JO - Translational Oncology
JF - Translational Oncology
IS - 6
ER -