This thesis, supervised by Rafael Sanjuán, has investigated the various mechanisms of cellular resistance to oncolytic viruses, a fundamental knowledge given the therapeutic applications of these viruses. Part of the research results have been published in the journals iScience i Scientific Reports. The thesis was defended on December 18, 2024.
Oncolytic viruses (OVs) represent a promising therapeutic strategy against cancer due to their ability to selectively destroy tumor cells, stimulate the anti-tumor immune response and act in combination with other treatments. However, some tumor cells develop resistance to OVs, which limits their effectiveness. The present PhD thesis, entitled “Cellular resistance to vesicular stomatitis virus (VSV): Implications for oncolytic virotherapy”, focused on the analysis of cellular resistance to VSV-D51, a variant of vesicular stomatitis virus with high oncolytic potential, in murine and human cellular models. Repeated exposure to VSV in two murine lines allowed the selection of resistant populations that showed massive gene reprogramming. Most of the resistant populations showed a chronic increase in the expression of interferon-stimulated genes, even without infection, while another population did not show this activation, revealing the existence of heterogeneous resistance mechanisms. In addition, the evaluation of the experimental evolution of the virus showed that VSV can adapt to break resistances without fixed changes in its genome. In cells with chronic immune activation, the adapted virus induced overexpression of inflammatory genes, whereas, in those with non-immune-mediated resistance, a decrease in the expression of interferon-related genes was observed. These findings were transferred to human models, identifying cell populations resistant to VSV. Their resistance profiles were characterized and the role of five genes associated with murine resistance was evaluated. Although these genes showed limited effect against infection with VSV-D51, they did not interfere with infection with the wild-type variant or Sindbis virus. Taken together, this research highlights the importance of understanding the mechanisms of resistance to OVs, which can vary widely between cells and transcriptomic contexts. Given the potential that OVs have demonstrated in combination therapies and their validity as platforms for vaccine development, studies on cellular resistance to OVs are essential to improve their applicability and clinical translation.
Alejandra Larrieux conducted her doctoral research in the Evolutionary Virology group under the supervision of Rafael Sanjuán, professor at the Department of Genetics of the University of Valencia and researcher at the Institute of Integrative Systems Biology I2SysBio (UV-CSIC). During the development of her thesis, Alejandra Larrieux enjoyed a contract of the Research Staff Training Program (FPI) of the Ministry of Science, Innovation and Universities. The examining board was formed by José Manuel Cuevas (I2SysBio), Josep Sardanyés (Centre de Recerca Matemàtica CRM) and Leonor Fernández-Murga (Hospital Arnau de Vilanova and CEU), who graded the thesis as outstanding.
