Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

Miriam I. Rosenberg; Erez Greenstein; Martin Buchkovich; Ayelet Peres; Eric Santoni-Rugiu; Lei Yang; Martin Mikl; Zalman Vaksman; David L. Gibbs; Dan Reshef; Amy Salovin; Meredith S. Irwin; Arlene Naranjo; Igor Ulitsky; Pedro A. de Alarcon; Katherine K. Matthay; Victor Weigman; Gur Yaari; Jessica A. Panzer; Nir Friedman; John M. Maris

doi:10.1016/j.celrep.2023.112879

Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

Miriam I. Rosenberg, Erez Greenstein, Martin Buchkovich, Ayelet Peres, Eric Santoni-Rugiu, Lei Yang, Martin Mikl, Zalman Vaksman, David L. Gibbs, Dan Reshef, Amy Salovin, Meredith S. Irwin, Arlene Naranjo, Igor Ulitsky, Pedro A. de Alarcon, Katherine K. Matthay, Victor Weigman, Gur Yaari, Jessica A. Panzer, Nir FriedmanJohn M. Maris

Department of Human Biology

Research output: Contribution to journal › Article › peer-review

Abstract

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 and showed that both were polyclonal expansions. Tertiary lymphoid structures (TLSs) were enriched in OMAS-associated tumors. We identified significant enrichment of the major histocompatibility complex (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 auto-reactive B lymphocytes act as antigen-presenting cells and drive TLS formation, thereby supporting both sustained polyclonal T cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.

Original language	English
Article number	112879
Journal	Cell Reports
Volume	42
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2023.112879
State	Published - 29 Aug 2023

Bibliographical note

Funding Information:
This work was funded by grants to M.I.R. and J.A.P. from the Pablove Foundation , the Rally Foundation , Open Hands/Overflowing Hearts Foundation , and The Truth 365 Foundation . This work was also funded by NIH grant R35 CA220500 (J.M.M.), the Giulio D’Angio Endowed Chair (J.M.M.) and RC1MD004418 to the NCI-TARGET consortium ( COG SDC grant U10 CA180899 ), NCTN Operations Center grant U10CA180886 and NCTN Statistics & Data Center grant U10CA180899 , and support from St. Baldrick's Foundation to Children’s Oncology Group .

Publisher Copyright:
© 2023 The Authors

Keywords

ataxia
autoimmunity
CP: Cancer
CP: Immunology
IgH
immune profiling
myoclonus
neuroblastoma
opsoclonus
paraneoplastic
repertoires
TCRB

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2023.112879

Cite this

Rosenberg, M. I., Greenstein, E., Buchkovich, M., Peres, A., Santoni-Rugiu, E., Yang, L., Mikl, M., Vaksman, Z., Gibbs, D. L., Reshef, D., Salovin, A., Irwin, M. S., Naranjo, A., Ulitsky, I., de Alarcon, P. A., Matthay, K. K., Weigman, V., Yaari, G., Panzer, J. A., ... Maris, J. M. (2023). Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma. Cell Reports, 42(8), Article 112879. https://doi.org/10.1016/j.celrep.2023.112879

@article{b7ba786ecab14d10a2cb0f280cc727f8,

title = "Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma",

abstract = "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 and showed that both were polyclonal expansions. Tertiary lymphoid structures (TLSs) were enriched in OMAS-associated tumors. We identified significant enrichment of the major histocompatibility complex (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 auto-reactive B lymphocytes act as antigen-presenting cells and drive TLS formation, thereby supporting both sustained polyclonal T cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.",

keywords = "ataxia, autoimmunity, CP: Cancer, CP: Immunology, IgH, immune profiling, myoclonus, neuroblastoma, opsoclonus, paraneoplastic, repertoires, TCRB",

author = "Rosenberg, {Miriam I.} and Erez Greenstein and Martin Buchkovich and Ayelet Peres and Eric Santoni-Rugiu and Lei Yang and Martin Mikl and Zalman Vaksman and Gibbs, {David L.} and Dan Reshef and Amy Salovin and Irwin, {Meredith S.} and Arlene Naranjo and Igor Ulitsky and {de Alarcon}, {Pedro A.} and Matthay, {Katherine K.} and Victor Weigman and Gur Yaari and Panzer, {Jessica A.} and Nir Friedman and Maris, {John M.}",

note = "Funding Information: This work was funded by grants to M.I.R. and J.A.P. from the Pablove Foundation , the Rally Foundation , Open Hands/Overflowing Hearts Foundation , and The Truth 365 Foundation . This work was also funded by NIH grant R35 CA220500 (J.M.M.), the Giulio D{\textquoteright}Angio Endowed Chair (J.M.M.) and RC1MD004418 to the NCI-TARGET consortium ( COG SDC grant U10 CA180899 ), NCTN Operations Center grant U10CA180886 and NCTN Statistics & Data Center grant U10CA180899 , and support from St. Baldrick's Foundation to Children{\textquoteright}s Oncology Group . Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = aug,

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doi = "10.1016/j.celrep.2023.112879",

language = "English",

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Rosenberg, MI, Greenstein, E, Buchkovich, M, Peres, A, Santoni-Rugiu, E, Yang, L, Mikl, M, Vaksman, Z, Gibbs, DL, Reshef, D, Salovin, A, Irwin, MS, Naranjo, A, Ulitsky, I, de Alarcon, PA, Matthay, KK, Weigman, V, Yaari, G, Panzer, JA, Friedman, N & Maris, JM 2023, 'Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma', Cell Reports, vol. 42, no. 8, 112879. https://doi.org/10.1016/j.celrep.2023.112879

TY - JOUR

T1 - Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

AU - Rosenberg, Miriam I.

AU - Greenstein, Erez

AU - Buchkovich, Martin

AU - Peres, Ayelet

AU - Santoni-Rugiu, Eric

AU - Yang, Lei

AU - Mikl, Martin

AU - Vaksman, Zalman

AU - Gibbs, David L.

AU - Reshef, Dan

AU - Salovin, Amy

AU - Irwin, Meredith S.

AU - Naranjo, Arlene

AU - Ulitsky, Igor

AU - de Alarcon, Pedro A.

AU - Matthay, Katherine K.

AU - Weigman, Victor

AU - Yaari, Gur

AU - Panzer, Jessica A.

AU - Friedman, Nir

AU - Maris, John M.

N1 - Funding Information: This work was funded by grants to M.I.R. and J.A.P. from the Pablove Foundation , the Rally Foundation , Open Hands/Overflowing Hearts Foundation , and The Truth 365 Foundation . This work was also funded by NIH grant R35 CA220500 (J.M.M.), the Giulio D’Angio Endowed Chair (J.M.M.) and RC1MD004418 to the NCI-TARGET consortium ( COG SDC grant U10 CA180899 ), NCTN Operations Center grant U10CA180886 and NCTN Statistics & Data Center grant U10CA180899 , and support from St. Baldrick's Foundation to Children’s Oncology Group . Publisher Copyright: © 2023 The Authors

PY - 2023/8/29

Y1 - 2023/8/29

N2 - 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 and showed that both were polyclonal expansions. Tertiary lymphoid structures (TLSs) were enriched in OMAS-associated tumors. We identified significant enrichment of the major histocompatibility complex (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 auto-reactive B lymphocytes act as antigen-presenting cells and drive TLS formation, thereby supporting both sustained polyclonal T cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.

AB - 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 and showed that both were polyclonal expansions. Tertiary lymphoid structures (TLSs) were enriched in OMAS-associated tumors. We identified significant enrichment of the major histocompatibility complex (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 auto-reactive B lymphocytes act as antigen-presenting cells and drive TLS formation, thereby supporting both sustained polyclonal T cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology.

KW - ataxia

KW - autoimmunity

KW - CP: Cancer

KW - CP: Immunology

KW - IgH

KW - immune profiling

KW - myoclonus

KW - neuroblastoma

KW - opsoclonus

KW - paraneoplastic

KW - repertoires

KW - TCRB

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U2 - 10.1016/j.celrep.2023.112879

DO - 10.1016/j.celrep.2023.112879

M3 - Article

C2 - 37537844

AN - SCOPUS:85166618346

SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 8

M1 - 112879

ER -

Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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