Entire requirement of endogenous type I Interferon for the efficacious cancer treatment with viral vector-encoded IL-12
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1
Fundacion para la Investigacion Medica Aplicada, Universidad de Navarra, Gene Therapy and Hepatology, Spain
To date little is known about how the innate IFNα/β response affects the efficacy of cancer treatments based in viral vector delivery of therapeutic genes. Using Semliki Forest virus encoding IL-12 (SFV/IL-12), a promising RNA viral vector for tumor treatment, we have explored this. Intratumoral injection of SFV/IL-12 induces production of IFNα/ that is readily detected in serum. Such production is abolished in interferon-beta promoter stimulator 1 (IPS1)ko mice and to some extent in TIR-domain-containing adapter-inducing IFN-β (TRIF)ko mice. Using bone-marrow chimeric mice we show that both hematopoietic and stromal cells are involved in the IFNα/β response. Macrophages, plasmacytoid and conventional dendritic cells are all implicated in the IFNα/β production, as was revealed by depleting experiments. The therapeutic activity of SFV/IL-12 against MC38 tumor is absolutely lost in mice deficient for the IFNα/β receptor (IFNAR) and when IFNAR signaling is blocked in vivo with anti-IFNAR mAb. This is also true for TC1 tumor. The lack of efficacy is not related to an impaired expression of IL-12 because IFNARko mice even express higher levels of the transgene. IFNAR absolute requirement is mainly operational at hematopoietic-derived cells. Interestingly, tumor-specific CTLs are outstandingly expanded upon SFV/IL-12 intratumoral injection to WT mice, but this does not happen when tumor-bearing mice are IFNARko, or have been treated with anti-IFNAR mAb. All in all, our data show that the efficacy of tumor immunotherapy with SFV/IL-12 is totally dependent on IFNS-I and unravels an unexpected mechanism of action of a therapy that is being translated to patients.
Keywords:
IFNα/β,
CTL,
Immunotherapy, Active,
Gene Therapy,
Cancer
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Translational immunology and immune intervention
Citation:
Hervas Stubbs
S,
Quetglas
J,
Rodríguez-Madoz
JR,
Mancheno
U,
Casales
E,
Riezu-Boj
J,
Ochoa
C,
Fernández De Sanmamed
M,
Smerdou
C and
Melero
I
(2013). Entire requirement of endogenous type I Interferon for the efficacious cancer treatment with viral vector-encoded IL-12.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00830
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Received:
21 Jun 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Dr. Sandra Hervas Stubbs, Fundacion para la Investigacion Medica Aplicada, Universidad de Navarra, Gene Therapy and Hepatology, Pamplona, Spain, mshervas@unav.es