EPIGENETIC REPROGRAMMING IN ADULT AND PEDIATRIC GLIOMAS LEADS TO ENHANCED RESPONSE TO IMMUNE-MEDIATED THERAPIES

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Maria G Castro1,2,3

1Department of Neurosurgery and Cell and Developmental Biology, Rogel Cancer Center, 2Immunology Graduate Program, 3Cancer Biology Graduate Program, University of Michigan Medical School

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Mutation in isocitrate dehydrogenase (mIDH) is a common genetic lesion encountered in glioma patients, resulting in a single amino acid change from arginine to histidine (R132H). IDH1/2 mutations exert a dominant gain of function enzymatic activity which leads to the production of 2-hydroxyglutarate (2HG). Production of 2HG causes DNA hypermethylation via inhibition of methylcytosine dioxygenase TET2 and also promotes histone hypermethylation through competitive inhibition of α-ketoglutarate (αKG)-dependent Jumonji-C histone demethylases, leading to epigenetic reprogramming.

 

Our work has shown that mutant mIDH1 leads to reprogramming of the glioma cells’ transcriptome, mediated by epigenetic mechanisms. This in turn ensures the reversion of the glioma immunosuppressive microenvironment due to changes in the cytokine profile secreted by glioma cells. We uncovered that the immature myeloid cells infiltrating the mIIDH1 TME are mainly non-suppressive neutrophils and pre-neutrophils. Reprogramming of myelopoiesis was triggered by granulocyte colony-stimulating factor (G-CSF) secreted by mIDH1 glioma stem-like cells. Blocking G-CSF in mIDH1 glioma-bearing mice restores the inhibitory potential of myeloid cells, accelerating tumor progression. Also, we demonstrated that G-CSF reprograms bone-marrow granulopoiesis resulting in non-inhibitory myeloid cells that infiltrate the mIDH1 glioma TME. This results in enhanced therapeutic efficacy of immune-stimulatory gene therapy (TK/Flt3L) in mIDH1 glioma. Our results uncover an important role of mIDH1 in reprogramming the phenotypic and functional diversity of myeloid cells in glioma TME, a feature that can be harnessed to enhance the efficacy of immunotherapies in glioma patients.

 

Diffuse hemispheric glioma (DHG), H3 G34-mutant, representing 9-15% of cases, are aggressive Central Nervous System (CNS) tumors with poor prognosis. We will discuss the role of epigenetic reprogramming of the immune microenvironment and the response to immune-mediated therapies in G34-mutant DHG. Our findings show that the G34 mutation alters histone marks' deposition at promoter and enhancer regions, leading to the activation of the JAK/STAT pathway, which in turn results in an immune-permissive tumor microenvironment. The implementation of Ad-TK/Ad-Flt3L immunostimulatory gene therapy significantly improved median survival and led to over 50% long-term survivors. Upon tumor rechallenge in the contralateral hemisphere without any additional treatment, the long-term survivors exhibited robust anti-tumor immunity and immunological memory. These results indicate that immune-mediated therapies hold significant potential for clinical translation in treating patients harboring H3.3-G34 mutant DHGs, offering a promising strategy for improving outcomes in this challenging cancer subtype affecting adolescents and young adults (AYA).