Mesenchymal and adrenergic cell lineage states in neuroblastoma possess distinct immunogenic phenotypes
Sengupta, Satyaki; Das, Sanjukta; Crespo, Angela C; Cornel, Annelisa M; Patel, Anand G; Mahadevan, Navin R; Campisi, Marco; Ali, Alaa K; Sharma, Bandana; Rowe, Jared H; Huang, Hao; Debruyne, David N; Cerda, Esther D; Krajewska, Malgorzata; Dries, Ruben; Chen, Minyue; Zhang, Shupei; Soriano, Luigi; Cohen, Malkiel A; Versteeg, Rogier; Jaenisch, Rudolf; Spranger, Stefani; Romee, Rizwan; Miller, Brian C; Barbie, David A; Nierkens, Stefan; Dyer, Michael A; Lieberman, Judy; George, Rani E
(2022) Nature Cancer, volume 3, issue 10, pp. 1228 - 1246
(Article)
Abstract
Apart from the anti-GD2 antibody, immunotherapy for neuroblastoma has had limited success due to immune evasion mechanisms, coupled with an incomplete understanding of predictors of response. Here, from bulk and single-cell transcriptomic analyses, we identify a subset of neuroblastomas enriched for transcripts associated with immune activation and inhibition and show
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that these are predominantly characterized by gene expression signatures of the mesenchymal lineage state. By contrast, tumors expressing adrenergic lineage signatures are less immunogenic. The inherent presence or induction of the mesenchymal state through transcriptional reprogramming or therapy resistance is accompanied by innate and adaptive immune gene activation through epigenetic remodeling. Mesenchymal lineage cells promote T cell infiltration by secreting inflammatory cytokines, are efficiently targeted by cytotoxic T and natural killer cells and respond to immune checkpoint blockade. Together, we demonstrate that distinct immunogenic phenotypes define the divergent lineage states of neuroblastoma and highlight the immunogenic potential of the mesenchymal lineage.
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Keywords: Oncology, Cancer Research, Journal Article
ISSN: 2662-1347
Publisher: Nature Research
Note: Funding Information: We thank C. Cardoso and M. Harlow from the George laboratory and S. Sen Santara, Y. Zhang and Z. Zhang from the Lieberman laboratory for helpful discussions. We thank M. Zimmerman, A. T. Look and K. Stegmaier for sharing cell lines. We thank the following members of the former Haining laboratory at DFCI for sharing resources and experimental advice: U. Gerdemann, D. Comstock, K. Yates, A. Word and A. Long. We thank F. Westermann’s group for sharing the Seurat object containing the count matrix derived from the snRNA-seq dataset. We thank H. Tillman and the St. Jude Veterinary Pathology Core for their assistance with IHC staining. The results shown here are in part based on data curated by the R2: Genomics Analysis and Visualization Platform: http://r2.amc.nl/. This work was supported by a St. Baldrick’s Foundation Childhood Cancer Research Grant, grant no. DOD CA191000 (R.E.G. and R.J.); NIH grant no. R01-CA197336 (R.E.G); and the Cookies for Kids’ Cancer Foundation (R.E.G); the Ted and Eileen Pasquarello Research Fund (R.R.); and Villa Joep Foundation, grant no. IWOV-Actief.51391.180034 (S.N.). S. Spranger is a recipient of a Pew Stewart Scholarship. S. Sengupta and M.K. were supported by the Rally Foundation for Childhood Cancer Research and Infinite Love for Kids Fighting Cancer, M. Campisi by an AIRC Fellowship for Abroad, B.C.M. by the National Center for Advancing Translational Sciences/NIH Award no. KL2 TR002542 and D.N.D. by an Alex’s Lemonade Stand Foundation Young Investigator Fellowship. Funding Information: We thank C. Cardoso and M. Harlow from the George laboratory and S. Sen Santara, Y. Zhang and Z. Zhang from the Lieberman laboratory for helpful discussions. We thank M. Zimmerman, A. T. Look and K. Stegmaier for sharing cell lines. We thank the following members of the former Haining laboratory at DFCI for sharing resources and experimental advice: U. Gerdemann, D. Comstock, K. Yates, A. Word and A. Long. We thank F. Westermann’s group for sharing the Seurat object containing the count matrix derived from the snRNA-seq dataset. We thank H. Tillman and the St. Jude Veterinary Pathology Core for their assistance with IHC staining. The results shown here are in part based on data curated by the R2: Genomics Analysis and Visualization Platform: http://r2.amc.nl/ . This work was supported by a St. Baldrick’s Foundation Childhood Cancer Research Grant, grant no. DOD CA191000 (R.E.G. and R.J.); NIH grant no. R01-CA197336 (R.E.G); and the Cookies for Kids’ Cancer Foundation (R.E.G); the Ted and Eileen Pasquarello Research Fund (R.R.); and Villa Joep Foundation, grant no. IWOV-Actief.51391.180034 (S.N.). S. Spranger is a recipient of a Pew Stewart Scholarship. S. Sengupta and M.K. were supported by the Rally Foundation for Childhood Cancer Research and Infinite Love for Kids Fighting Cancer, M. Campisi by an AIRC Fellowship for Abroad, B.C.M. by the National Center for Advancing Translational Sciences/NIH Award no. KL2 TR002542 and D.N.D. by an Alex’s Lemonade Stand Foundation Young Investigator Fellowship. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
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