Epigenetic regulation of cell state by H2AFY governs immunogenicity in high-risk neuroblastoma
Divya Nagarajan, Rebeca T. Parracho, David Corujo, Minglu Xie, Ginte Kutkaite, Thale K. Olsen, Marta Rubies Bedos, Maede Salehi, Ninib Baryawno, Michael P. Menden, Xingqi Chen, Marcus Buschbeck, Yumeng Mao
Divya Nagarajan, Rebeca T. Parracho, David Corujo, Minglu Xie, Ginte Kutkaite, Thale K. Olsen, Marta Rubies Bedos, Maede Salehi, Ninib Baryawno, Michael P. Menden, Xingqi Chen, Marcus Buschbeck, Yumeng Mao
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Research Article Immunology Oncology

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

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.

Authors

Divya Nagarajan, Rebeca T. Parracho, David Corujo, Minglu Xie, Ginte Kutkaite, Thale K. Olsen, Marta Rubies Bedos, Maede Salehi, Ninib Baryawno, Michael P. Menden, Xingqi Chen, Marcus Buschbeck, Yumeng Mao

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Figure 6

Concurrent activation of adaptive and innate immunity enabled antitumor immunity in H2afy-KO tumors.

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Concurrent activation of adaptive and innate immunity enabled antitumor ...
Control (ctrl) or KO 9464D tumors were harvested after the last dose of rat IgG2a isotype control or α-PD-1 antibody. Single cells were generated from tumors and mRNA were isolated for Nanostring analysis. Differentially expressed mRNAs were compared between KO and ctrl mice treated with (A) IgG or (B) α-PD1, via unpaired 2-tailed t test. (C and D) Genes were grouped according to functions and their expressions were shown for all groups. (E) Single cells were generated from mice bearing ctrl or KO 9464D tumors in different treatment groups (5–7 mice per group) and myeloid cells were characterized using flow cytometry. Statistical differences among groups were analyzed using a 2-way ANOVA. (F) Single cells from mice bearing KO 9464D tumors treated with a rat IgG isotype control (n = 4) or the α-PD-1 antibody (n = 6) were isolated and activation of myeloid cells was characterized using flow cytometry, unpaired 2-tailed t test.