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Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

View ORCID ProfileMI Rosenberg, View ORCID ProfileE Greenstein, View ORCID ProfileM Buchkovich, View ORCID ProfileM Mikl, A Peres, View ORCID ProfileE Santoni-Rugiu, D Reshef, A Salovin, View ORCID ProfileDL Gibbs, MS Irwin, View ORCID ProfileA Naranjo, View ORCID ProfileI Ulitsky, PA de Alarcon, View ORCID ProfileV Weigman, View ORCID ProfileG Yaari, JA Panzer, N Friedman, View ORCID ProfileJM Maris
doi: https://doi.org/10.1101/2021.12.14.471886
MI Rosenberg
1Hebrew University of Jerusalem, Edmond Safra Campus, Givat Ram, Jerusalem 91904 Israel
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  • For correspondence: maris@chop.edu miriam.rosenberg1@mail.huji.ac.il
E Greenstein
2Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
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M Buchkovich
3Q2 Solutions, Morrisville, North Carolina, USA
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M Mikl
4Department of Human Biology, Faculty of Natural Sciences, University of Haifa, Mount Carmel, Haifa 31905, Israel
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A Peres
5Faculty of Engineering, Bar Ilan University, Ramat Gan 5290002, Israel
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E Santoni-Rugiu
6Department of Pathology, Rigshospitalet, Copenhagen, University Hospital and Biotech Research & Innovation Center, Copenhagen University, Copenhagen 2100, Denmark
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D Reshef
2Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
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A Salovin
7Division of Neurology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia PA 19104, USA
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DL Gibbs
8ISB, 401 Terry Ave. N. Seattle, WA 98109 USA
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MS Irwin
9Department of Pediatrics and Division of Hematology-Oncology, Hospital for Sick Children, University of Toronto, 555 University Ave, Toronto, ON M5G1X8, Canada
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A Naranjo
10Department of Biostatistics, University of Florida, Children’s Oncology Group Statistics & Data Center, Gainesville, FL USA
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I Ulitsky
11Department of Biological Regulation, Weizmann Institute of Science, Rehovot 7610001, Israel
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PA de Alarcon
12Department of Pediatric Hematology/Oncology, University of Illinois School of Medicine, Peoria, IL 61605, USA
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V Weigman
3Q2 Solutions, Morrisville, North Carolina, USA
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G Yaari
5Faculty of Engineering, Bar Ilan University, Ramat Gan 5290002, Israel
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JA Panzer
7Division of Neurology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia PA 19104, USA
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N Friedman
2Department of Immunology, Weizmann Institute of Science, Rehovot 7610001, Israel
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JM Maris
13Department of Pediatrics and Division of Oncology, Children’s Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania, Philadelphia PA 19104, USA
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  • For correspondence: maris@chop.edu miriam.rosenberg1@mail.huji.ac.il
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Summary

Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop Opsoclonus Myoclonus Ataxia Syndrome (OMAS), a paraneoplastic disease characterized by cerebellar and brainstem-directed autoimmunity, but typically with outstanding cancer-related outcomes. We compared tumor transcriptomes and tumor infiltrating T- and B-cell repertoires from 38 OMAS subjects with neuroblastoma to 26 non- OMAS associated neuroblastomas. We found greater B- and T-cell infiltration in OMAS- associated tumors compared to controls, but unexpectedly showed that both were polyclonal expansions. Tertiary lymphoid structures (TLS) were enriched in OMAS-associated tumors. We identified significant enrichment of the MHC Class II allele HLA-DOB*01:01 in OMAS patients. OMAS severity scores were associated with the expression of several candidate autoimmune genes. We propose a model in which polyclonal autoreactive B lymphocytes act as antigen presenting cells and drive TLS formation, thereby crucially supporting both sustained polyclonal T-cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 14, 2021.
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Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma
MI Rosenberg, E Greenstein, M Buchkovich, M Mikl, A Peres, E Santoni-Rugiu, D Reshef, A Salovin, DL Gibbs, MS Irwin, A Naranjo, I Ulitsky, PA de Alarcon, V Weigman, G Yaari, JA Panzer, N Friedman, JM Maris
bioRxiv 2021.12.14.471886; doi: https://doi.org/10.1101/2021.12.14.471886
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Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma
MI Rosenberg, E Greenstein, M Buchkovich, M Mikl, A Peres, E Santoni-Rugiu, D Reshef, A Salovin, DL Gibbs, MS Irwin, A Naranjo, I Ulitsky, PA de Alarcon, V Weigman, G Yaari, JA Panzer, N Friedman, JM Maris
bioRxiv 2021.12.14.471886; doi: https://doi.org/10.1101/2021.12.14.471886

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