TMIC-70 - A transcriptionally active epigenetic imprinting of the JAK/STAT pathway mediated by H3.3-G34 mutations in pediatric high-grade glioma (pHGG) induces an immunoreactive TME

Friday, November 17, 2023

7:30 PM – 9:30 PM PT

Location: Exhibit Hall A/B

Poster Presenter(s)

Santiago Haase

Department of Neurosurgery, Department of Cell and Developmental Biology, University of Michigan
Ann Arbor, Michigan, United States

Author(s)

MG

Maria Belen Garcia Fabiani

University of Michigan
Ann Arbor, United States
KB

Kausjik Banerjee

University of Michigan
Ann Arbor, United States
AM

Anzar Abdul Mujeeb

University of Michigan
Ann Arbor, United States
YL

Yingxiang Li

University of Michigan
Ann Arbor, United States
ZZ

Ziwen Zhu

University of Michigan
Ann Arbor, Michigan, United States
FN

Felipe Nunez

University of Michigan
Ann Arbor, United States
Jennifer Yu

Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic
Cleveland, Ohio, United States
Pedro R. Lowenstein

Department of Neurosurgery, and Cell and Developmental Biology, Rogel Cancer Center, University of Michigan Medical School
Ann Arbor, Michigan, United States
Maria G. Castro

University of Michigan Medical School
Ann Arbor, Michigan, United States

Pediatric high-grade gliomas (pHGGs) stand as the primary cause of cancer-associated fatalities among children. Sixteen percent of pHGGs found in children and young adults present Gly34Arg/Val substitutions within the histone H3.3 (H3.3-G34R/V). Using a syngeneic, genetically engineered mouse model (GEMM) and human pHGG cells encoding H3.3-G34R, we showed that this mutation leads to downregulation of the DNA repair pathways and enhanced susceptibility to DNA damage. DNA damage response (DDR) inhibitors in vivo, further increased genetic instability, and activation of the cGAS-STING pathway, which induces the release of immune-stimulatory cytokines. We carried out an epigenetic analysis using ChIP-seq in our GEMM, and our findings indicate that this mutation triggers transcriptionally active chromatin states within genes linked to immune reactivity, particularly JAK-STAT signaling pathway genes. Correspondingly, G34-mutant pHGG cells release immune-activating cytokines that reprogram the immune cells within the tumor microenvironment (TME). Myeloid derived suppressor cells from G34-mutant pHGG are phenotypically less immunosuppressive than the MDCS form histone wild type pHGG. Moreover, G34-mutant pHGG TME exhibit higher frequency of CD8 T cells. Based on these findings, we assessed the efficacy of an adenoviral-mediated immunostimulatory gene therapy (GT). This therapy mediates expression of Flt3L within pHGG TME, which aids dendritic cell recruitment. Thymidine kinase (TK), converts ganciclovir (GSV) into a cytotoxic compound, leading to pHGG cells’ death. GT resulted in 60% of long-term survival in mice harboring G34R pHGG. The animals that survived due to the GT did not develop tumors after a rechallenge with G34R pHGG cells, demonstrating that the treatment induces antitumoral immunological memory. In conclusion, our findings suggest that G34-mutant pHGG patients could benefit from combined therapies that target genetic instability and stimulate the immune system. Funded by NIH/NINDS.