Radiation-induced antitumor immunity and type I interferon response in syngenic cancer models

Résumé

Triggering immunity to eliminate cancer cells throughout the body is a highly promising avenue in modern cancer research. The induction of adaptive antitumor immunity is essential for the specific and systemic eradication of cancer cells and for the formation of an antitumor immune memory to prevent cancer relapse. A growing number of studies propose that specific parameters of radiotherapy such as the type of radiation (X-rays vs. charged particles), dose and fractionation influence the anti-tumor immune response. While irradiation with charged particles provides advantages over X-ray irradiation, such as better ballistics and enhanced cancer cell death, it also induces different cellular responses which could ultimately lead to a stronger immunogenic response. The aim of this project is therefore to study and compare the immunogenicity induced by X-ray and high LET proton irradiation at different doses in syngeneic murine cancer models. To this end, the first part of this project aimed to assess the survival rates of three murine cancer cell lines irradiated with X-rays or protons and to determine the relative biological effectiveness (RBE) of protons. The second objective is to analyze the activation of cGAS/STING pathway under different irradiation conditions. Hence, cytosolic release of dsDNA, was investigated by immunofluorescent labeling as it triggers the cGAS/STING pathway. This activation leads to a type I interferon response. By RT-qPCR analysis, different components of this pathway were investigated after irradiation. The results indicate the activation of the cGAS/STING pathway in some experimental conditions. Additionally, the induction of immune-suppressive mechanisms in response to radiation was assessed following the expression of genes coding for immune-suppressive mediators. The expression of immunosuppressive genes after irradiation showed different effects in the three cancer cell lines. In the last part of the project, an in vivo vaccination assay comparing X-ray and proton irradiation alone or in combination with an anti-CTLA4 treatment was performed in order to evaluate the induction of systemic anti-tumor immunity. The secondary tumor development rate as well as the percentage of survival of mice indicate the establishment of an efficient immune response after X-ray and proton irradiation. A better effect was demonstrated after X-ray irradiation in combination or not with an anti-CTLA4 antibody. In conclusion, these results showed that an immune response could be induced by irradiation and that it depended on several irradiation parameters. Moreover, different effects were observed between cell lines meaning that biological effects after irradiation are dependent on the tumor model.

la date de réponse	17 janv. 2023
langue originale	Anglais
L'institution diplômante	Universite de Namur
Superviseur	Carine Michiels (Promoteur)