Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma
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.
Authors
- Marta Rúbies Bedós (ORCID: https://orcid.org/0000-0003-0949-4329)
- Yumeng Mao (ORCID: https://orcid.org/0000-0001-6142-6628)
- Thale Kristin Olsen (ORCID: https://orcid.org/0000-0003-4655-7384)
- Marcus Buschbeck (ORCID: https://orcid.org/0000-0002-3218-4567)
- Ninib Baryawno
- Michael P. Menden (ORCID: https://orcid.org/0000-0003-0267-5792)
- Xingqi Chen (ORCID: https://orcid.org/0000-0002-5657-2839)
- Ginte Kutkaite (ORCID: https://orcid.org/0000-0002-2918-294X)
- David Corujo (ORCID: https://orcid.org/0000-0001-7930-0935)
- Divya Nagarajan (ORCID: https://orcid.org/0000-0003-4348-9742)
- Maede Salehi (ORCID: https://orcid.org/0000-0003-0587-6952)
- Rebeca T Parracho
- Minglu Xie
Institutions
- Uppsala University (SE)
- The University of Melbourne (AU)
- Science for Life Laboratory (SE)
- Karolinska Institutet (SE)
- Helmholtz Zentrum München (DE)
- Josep Carreras Leukaemia Research Institute (ES)
- Pediatrics and Genetics (US)
- Ludwig-Maximilians-Universität München (DE)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2024-09-10
- DOI
- https://doi.org/10.1172/jci175310
- Citations
- 3
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.11
Funders
- AstraZeneca
- Universitetet i Tromsø
- Swedish Cancer Foundation
- European Commission
- Stiftelsen för Strategisk Forskning
- Cancerfonden
- Karolinska Institutet
- Knut och Alice Wallenbergs Stiftelse
- Novo Nordisk
- Vetenskapsrådet
- Barncancerfonden
- Uppsala Universitet
- Science for Life Laboratory
- European Regional Development Fund
- Agencia Estatal de Investigación
- Uppsala Multidisciplinary Center for Advanced Computational Science
- H2020 European Research Council