Abstract 2632: A new paradigm for brain tumors treatment: Guadecitabine as a fundamental player to improve tumor immune response
Authors: Lofiego Maria Fortunata , Piazzini Francesca , Caruso Francesca Pia , Marzani Francesco , Solmonese Laura , Bello Emma , Celesti Fabrizio , Costa Maria Claudia , Noviello Teresa Maria , Mortarini Roberta , Anichini Andrea , Ceccarelli Michele , Coral Sandra , Giacomo Anna Maria Di , Maio Michele , Covre Alessia 
Published: March 2024

Abstract
Background:Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor refractory to standard treatments and to immunotherapy with immune-checkpoint inhibitors (ICI) (PMID: 35626018). Interestingly, melanoma brain metastases (MM-BM), sharing the same niche as GBM, often respond to current ICI immunotherapies (PMID: 36521332). The role of epigenetic modifications in regulating GBM cellular proliferation, invasion, and prognosis, as well as their impact on the cross-talk between GBM and immune cells in the tumor milieu, has become evident (PMID: 34361090). Consequently, manipulating the epigenome has emerged as a therapeutic opportunity in GBM.
Methods:Microarray transcriptional and methylation profiles, followed by gene set enrichment and IPA analyses, were conducted to study the differences in constitutive expression profiles between GBM and MM-BM cells compared to extracranial MM cells. Additionally, the modulatory effects of the DNA hypomethylating agent (DHA) guadecitabine on different tumor cells were investigated. The prognostic relevance of DHA-modulated genes was assessed through Cox analysis in a TCGA GBM patients' cohort.
Results:The most notable differences between constitutive GBM and MM-BM cells lie in the enrichment of biological processes associated with tumor growth, invasion, and extravasation, as well as the inhibition of MHC class II antigen processing/presentation in GBM cells. Guadecitabine treatment appeared to shrink these differences, shifting the phenotype of GBM cells towards the more immunogenic MM-BM profile. This was achieved through promoter hypomethylation and subsequent up-regulation of genes mainly associated with the activation, proliferation, and migration of T and B cells, along with MHC class II antigen processing/presentation. Among DHA-modulated genes in GBM, 7.6% exhibited significant prognostic relevance. Moreover, a substantial set of immune-related upstream regulators (URs) were commonly modulated by DHA in GBM, MM-BM, and/or MM cells: DHA-activated URs enriched biological processes mainly involved in the regulation of cytokines and chemokines production, inflammatory response, and Type I/II/III IFN-mediated signaling. DHA-inhibited URs were associated with metabolic and proliferative pathways.
Conclusions:Epigenetic remodeling of GBM by DHA represents a promising strategy to enhance the efficacy of cancer immunotherapy, supporting the rationale for developing new combinatorial approaches for the treatment of brain malignancies.
Citation Format: Maria Fortunata Lofiego, Francesca Piazzini, Francesca Pia Caruso, Francesco Marzani, Laura Solmonese, Emma Bello, Fabrizio Celesti, Maria Claudia Costa, Teresa Maria Noviello, Roberta Mortarini, Andrea Anichini, Michele Ceccarelli, Sandra Coral, Anna Maria Di Giacomo, Michele Maio, Alessia Covre. A new paradigm for brain tumors treatment: Guadecitabine as a fundamental player to improve tumor immune response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2632.