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AKT and JUN are differentially activated in mesenchymal stem cells after infection with human and canine oncolytic adenoviruses

Cancer Gene Therapy volume 28, pages 64–73 (2021)Cite this article

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Abstract

There is increasing evidence about the use of oncolytic adenoviruses (Ads) as promising immunotherapy agents. We have previously demonstrated the clinical efficiency of mesenchymal stem cells (MSCs) infected with oncolytic Ads as an antitumoral immunotherapy (called Celyvir) in human and canine patients, using ICOVIR-5 or ICOCAV17 as human and canine oncolytic Ads, respectively. Considering the better clinical outcomes of canine patients, in this study we searched for differences in cellular responses of human and canine MSCs to Ad infection that may help understand the mechanisms leading to higher antitumor immune response. We found that infection of human and canine MSCs with ICOVIR-5 or ICOCAV17 did not activate the NF-κB pathway or the interferon regulatory factors IRF3 and IRF7. However, we observed differences in the profile of cytokines secretion, as infection of canine MSCs with ICOCAV17 resulted in lower secretion of several cytokines. Moreover, we showed that infection of human MSCs with ICOVIR-5 increased the phosphorylation of a number of proteins, including AKT and c-JUN. Finally, we demonstrated that differences in regulation of AKT and c-JUN in human and canine MSCs by ICOVIR-5 or ICOCAV17 are intrinsic to each virus. Our findings suggest that ICOCAV17 induces a more limited host response in canine MSCs, which may be related to a better clinical outcome. This result opens the possibility to develop new human oncolytic Ads with these specific properties. In addition, this improvement could be imitated by selecting specific human MSC on the basis of a limited host response after Ad infection.

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Fig. 1: NF-KB signaling pathway activity and IRFs phosphorylation after adenoviral infection of human and canine MSCs.
Fig. 2: Array analysis of secreted cytokines in human and canine MSCs after Ad infection.
Fig. 3: Signaling pathways regulated by Ad infection in human and canine MSCs.
Fig. 4: Differences in replication and signaling between ICOVIR-5 and ICOCAV17 depending on cell host.

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Acknowledgements

We thank Isabel Cubillo Moreno for her technical support in the study.

Funding

This study was funded by Instituto de Salud Carlos III (PI14CIII/00005 and PI17CIII/00013 grants), Consejería de Educación, Juventud y Deporte of Comunidad de Madrid (P2017/BMD-3692 grant), Fundación Oncohematología Infantil, AFANION, and Asociación Pablo Ugarte, whose support we gratefully acknowledge.

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  1. Cellular Biotechnology Unit, Instituto de Salud Carlos III, 28220, Madrid, Spain

    Miguel Ángel Rodríguez-Milla, Alvaro Morales-Molina, Ana Judith Perisé-Barrios, Teresa Cejalvo & Javier García-Castro

  2. Biomedical Research Unit, Universidad Alfonso X el Sabio, 28691, Madrid, Spain

    Ana Judith Perisé-Barrios

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  1. Miguel Ángel Rodríguez-Milla
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Correspondence to Javier García-Castro.

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Rodríguez-Milla, M.Á., Morales-Molina, A., Perisé-Barrios, A.J. et al. AKT and JUN are differentially activated in mesenchymal stem cells after infection with human and canine oncolytic adenoviruses. Cancer Gene Ther 28, 64–73 (2021). https://doi.org/10.1038/s41417-020-0184-9

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