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Nagarajan, D.* ; Parracho, R.T.* ; Corujo, D.* ; Xie, M.* ; Kutkaite, G. ; Olsen, T.K.* ; Rúbies Bedós, M.* ; Salehi, M.* ; Baryawno, N.* ; Menden, M.P. ; Chen, X.* ; Buschbeck, M.* ; Mao, Y.*

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

J. Clin. Invest.:e175310 (2024)

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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 neuroblastoma patients 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 sequencing 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 multi-omics approach, we uncover 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.

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