H3.3-G34R Mutation-Mediated Epigenetic Reprogramming Leads to Enhanced Efficacy of Immune Stimulatory Gene Therapy in Pediatric High-Grade Gliomas

• Published in: bioRxiv
• Main Authors: Garcia-Fabiani, Maria B, Haase, Santiago, Banerjee, Kaushik, McClellan, Brandon, Zhu, Ziwen, Mujeeb, Anzar, Li, Yingxiang, Yu, Jin, Kadiyala, Padma, Taher, Ayman, Núñez, Felipe J, Alghamri, Mahmoud S, Comba, Andrea, Mendez, Flor M, Nicola Candia, Alejandro J, Salazar, Brittany, Koschmann, Carl, Nunez, Fernando M, Edwards, Marta, Qin, Tingting, Sartor, Maureen A, Lowenstein, Pedro R, Castro, Maria G
• Format: Journal Article
• Language: English
• Published: United States 13.06.2023
• ISSN: 2692-8205

Pediatric high-grade gliomas (pHGGs) are diffuse and highly aggressive CNS tumors which remain incurable, with a 5-year overall survival of less than 20%. Within glioma, mutations in the genes encoding the histones H3.1 and H3.3 have been discovered to be age-restricted and specific of pHGGs. This work focuses on the study of pHGGs harboring the H3.3-G34R mutation. H3.3-G34R tumors represent the 9-15% of pHGGs, are restricted to the cerebral hemispheres, and are found predominantly in the adolescent population (median 15.0 years). We have utilized a genetically engineered immunocompetent mouse model for this subtype of pHGG generated via the Sleeping Beauty-transposon system. The analysis of H3.3-G34R genetically engineered brain tumors by RNA-Sequencing and ChIP-Sequencing revealed alterations in the molecular landscape associated to H3.3-G34R expression. In particular, the expression of H3.3-G34R modifies the histone marks deposited at the regulatory elements of genes belonging to the JAK/STAT pathway, leading to an increased activation of this pathway. This histone G34R-mediated epigenetic modifications lead to changes in the tumor immune microenvironment of these tumors, towards an immune-permissive phenotype, making these gliomas susceptible to TK/Flt3L immune-stimulatory gene therapy. The application of this therapeutic approach increased median survival of H3.3-G34R tumor bearing animals, while stimulating the development of anti-tumor immune response and immunological memory. Our data suggests that the proposed immune-mediated gene therapy has potential for clinical translation for the treatment of patients harboring H3.3-G34R high grade gliomas.