2. Academic Validation
  3. Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma

Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma

  • J Clin Invest. 2024 Sep 10;134(21):e175310. doi: 10.1172/JCI175310.
Divya Nagarajan 1 2,  Rebeca T Parracho 1 2,  David Corujo 3,  Minglu Xie 2,  Ginte Kutkaite 4 5,  Thale K Olsen 2 6,  Marta Rubies Bedos 1 2,  Maede Salehi 2,  Ninib Baryawno 6,  Michael P Menden 4 7,  Xingqi Chen 2,  Marcus Buschbeck 3,  Yumeng Mao 1 2
Affiliations

Affiliations

  • 1 Science for Life Laboratory, Department of Immunology, Genetics and Pathology and.
  • 2 Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
  • 3 Program of Myeloid Neoplasms, Program of Applied Epigenetics, Josep Carreras Leukaemia Research Institute (IJC), Campus Can Ruti Site, Badalona, Spain.
  • 4 Computational Health Center, Helmholtz Munich, Neuherberg, Germany.
  • 5 Department of Biology, Ludwig-Maximilians University Munich, Martinsried, Germany.
  • 6 Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Solna, Sweden.
  • 7 Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, Australia.
PMID: 39255035 DOI: 10.1172/JCI175310
Abstract

Childhood neuroblastoma with MYCN amplification is classified as high risk and often relapses after intensive treatments. Immune Checkpoint blockade therapy against the PD-1/L1 axis shows limited efficacy in patients with neuroblastoma, and the Cancer intrinsic immune regulatory network is poorly understood. Here, we leverage genome-wide CRISPR/Cas9 screens and identify H2AFY as a resistance gene to the clinically approved PD-1 blocking antibody nivolumab. Analysis of single-cell RNA-Seq datasets reveals that H2AFY mRNA is enriched in adrenergic Cancer cells and is associated with worse patient survival. Genetic deletion of H2afy in MYCN-driven neuroblastoma cells reverts in vivo resistance to PD-1 blockade by eliciting activation of the adaptive and innate immunity. Mapping of the epigenetic and translational landscape demonstrates that H2afy deletion promotes cell transition to a mesenchymal-like state. With a multiomics approach, we uncovered H2AFY-associated genes that are functionally relevant and prognostic in patients. Altogether, our study elucidates the role of H2AFY as an epigenetic gatekeeper for cell states and immunogenicity in high-risk neuroblastoma.

Keywords

Cancer; Cancer immunotherapy; Immunology; Oncology.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16425
    99.86%, HDAC1/3 Inhibitor