Abstract 3263: Implications for cancer viroimmunotherapy: a new adenovirus capsid sensor

Abstract

Abstract The median survival for glioblastoma (GBM) patients is 12-15 months, with a five-year survival rate of less than 10% despite aggressive treatment with surgery, radiotherapy, and chemotherapy. Oncolytic virotherapy is emerging as a promising approach to reprogramming the immunosuppressed microenvironment of GBMs and restoring anti-tumor immunity. Delta-24-RGD is an oncolytic adenovirus that has shown favorable results in phase I clinical trials (NCT00805376; NCT03178032). However, immune responses functionally cleared the virus within weeks of administration, limiting anti-cancer efficacy to a subset (~20%) of patients. A better understanding of the innate immune response against adenoviruses may provide the rationale for developing improved anticancer approaches. Using bulk RNA sequencing, we have examined the transcriptome of normal lung fibroblasts infected with wild-type adenovirus. Ingenuity pathway analysis (IPA) showed upregulation of several immune response-related pathways, including interferon response factor 3 (IRF3). Interestingly, these analyses also showed an unexpected upregulation of the Non-POU Domain Containing Octamer Binding (NONO) pathway during adenoviral infection. In fact, upstream regulators analyses showed a 7-fold increase in the NONO pathway in two different cell lines. Increases in NONO expression changes in response to adenovirus treatment were validated by western blot. Furthermore, co-immunoprecipitation assays showed that NONO binds to adenoviral capsid proteins during infection and to the foreign DNA sensor cyclic GMP AMP synthase (cGAS), which is critical for the activation of the innate immunity, via IRF3. In our proposed model, NONO protein binds to the adenoviral capsid protein and associates with the sensor cGAS in the nucleus to enable sensing of viral nucleic acid. In conclusion, we uncovered a new mechanism for detecting adenovirus infection that involves the interaction of adenoviral capsid proteins with members of the NONO pathway in the nucleus of the infected cell. Further studies are in progress to examine to which extent adenoviruses unable to bind NONO may persist longer in the infected tumors than unmodified adenoviruses and whether the persistence of the virus in the tumor correlates with enhanced anti-glioma effect. Citation Format: Andrew Gregg Gillard, Dong Ho Shin, Virginia Laspidea, Hong Jiang, Fan Xuejun, Yanhua Yi, Marta M. Alonso, Juan Fueyo, Candelaria Gomez-Manzano. Implications for cancer viroimmunotherapy: a new adenovirus capsid sensor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3263.