Strict Requirement for Vector-Induced Type I Interferon in Efficacious Antitumor Responses to Virally Encoded IL12
| العنوان: | Strict Requirement for Vector-Induced Type I Interferon in Efficacious Antitumor Responses to Virally Encoded IL12 |
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| المؤلفون: | Uxua Mancheño, Juan R. Rodriguez-Madoz, Mercedes Reboredo, Marta Ruiz-Guillen, Nathalie Thieblemont, Maria C. Ochoa, Juan Dubrot, Ignacio Melero, Erkuden Casales, Sandra Hervas-Stubbs, José-Ignacio Riezu-Boj, Cristian Smerdou, Jose I. Quetglas, Miguel F. Sanmamed |
| المصدر: | Cancer Research. 75:497-507 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Cancer Research, Stromal cell, Transgene, Genetic Vectors, Green Fluorescent Proteins, Antineoplastic Agents, CD8-Positive T-Lymphocytes, Biology, Semliki Forest virus, Viral vector, Mice, Interferon, Cell Line, Tumor, medicine, Animals, Transgenes, Crosses, Genetic, Macrophages, Interferon-alpha, Dendritic Cells, Genetic Therapy, Interferon-beta, Flow Cytometry, biology.organism_classification, Interleukin-12, Virology, Recombinant Proteins, Mice, Inbred C57BL, Oncology, TRIF, Cancer research, Interleukin 12, RNA, Viral, Female, Immunotherapy, CD8, medicine.drug |
| الوصف: | 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 IFNβ transcriptional regulator IPS-1 and partially attenuated in mice deficient for the IFNβ 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 expanded robustly after intratumoral injection of WT mice with SFV-IL12, this did not occur in mice where IFNAR was inactivated genetically or pharmacologically. Overall, our results argued that the antitumor efficacy of a virally based transgene therapeutic relied strongly on a vector-induced IFN-I response, revealing an unexpected mechanism of action that is relevant to a broad array of current translational products in cancer research. Cancer Res; 75(3); 497–507. ©2014 AACR. |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e2eb76d56aea72051bbfa1eabaa465dd https://doi.org/10.1158/0008-5472.can-13-3356 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....e2eb76d56aea72051bbfa1eabaa465dd |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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