A short hairpin RNA-based adjuvant targeting NF-κB repressor IκBα promotes migration of dermal dendritic cells to draining lymph nodes and antitumor CTL responses induced by DNA vaccination
| Autor: | Camila Flores, Felipe Gálvez-Cancino, Cesar Oyarce, Manuel Varas-Godoy, Paola Murgas, Sebastián Cruz-Gómez, Nicole Rojas-Colonelli, Daniela Sauma, Alvaro Lladser, Jonathan A. Roco |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Biology Cancer Vaccines DNA vaccination Small hairpin RNA 03 medical and health sciences 0302 clinical medicine Adjuvants Immunologic NF-KappaB Inhibitor alpha Antigen Cell Movement Vaccines DNA Animals Cytotoxic T cell RNA Small Interfering Lung Melanoma Innate immune system General Veterinary General Immunology and Microbiology Vaccination Public Health Environmental and Occupational Health Dendritic cell Molecular biology Mice Inbred C57BL Disease Models Animal IκBα CTL Treatment Outcome 030104 developmental biology Infectious Diseases Langerhans Cells 030220 oncology & carcinogenesis Cancer research Molecular Medicine Lymph Nodes T-Lymphocytes Cytotoxic |
| Zdroj: | Vaccine. 35:4148-4154 |
| ISSN: | 0264-410X |
| DOI: | 10.1016/j.vaccine.2017.06.041 |
| Popis: | DNA vaccination is an attractive approach to elicit tumor-specific cytotoxic CD8+ T lymphocytes (CTL), which can mediate protective immunity against tumors. To initiate CTL responses, antigen-encoding plasmids employed for DNA vaccination need to activate dendritic cells (DC) through the stimulation of DNA-sensing innate immune receptors that converge in the activation of the master transcription factor NF-κB. To this end, NF-κB repressor IκBα needs to be degraded, allowing NF-κB to translocate to the nucleus and transcribe proinflammatory target genes, as well as its repressor IκBα. Therefore, NF-κB activation is self-limited by de novo synthesis of IκBa, which sequesters NF-κB in the cytosol. Hence, we tested whether co-delivering a shRNA-based adjuvant able to silence IκBα expression would further promote DNA-induced NFκB activation, DC activation and tumor-protective CTL responses induced by DNA vaccination in a preclinical model. First, an IκBα-targeting shRNA plasmid (shIκBα) was shown to reduce IκBα expression and promote NFκB-driven transcription in vitro, as well as up-regulate inflammatory target genes in vivo. Then, we showed that intradermal DNA electroporation induced the migration of skin migratory dendritic cells to draining lymph nodes and maturation of dermal dendritic cells (dDC). Interestingly, shIκBα further promoted the migration of mature skin migratory dendritic cells, in particular dDC, which are specialized in antigen cross-presentation and activation of CD8+ T cells. Consistently, mice vaccinated with a plasmid encoding the melanoma-associated antigen tyrosinase-related protein 2 (TRP2) in combination with shIκBα enhanced TRP2-specific CTL responses and reduced the number of lung melanoma foci in mice challenged with intravenous injection of B16F10 cells. Moreover, therapeutic vaccination with pTRP2 and shIκBα delayed the growth of B16F10 melanoma subcutaneous tumors. Our data suggest that adjuvants promoting NF-κB activation represent an attractive strategy to boost DC activation and promote the generation of tumor-protective CTL responses elicited by DNA vaccines. |
| Databáze: | OpenAIRE |
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