Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

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

doi:10.1101/2021.12.14.471886

Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

Miriam I Rosenberg, Erez Greenstein, Martin Buchkovich, Martin Mikl, Ayelet Peres, Eric Santoni-Rugiu, Dan Reshef, Amy J Salovin, David L Gibbs, Meredith S Irwin, Arlene Naranjo, Igor Ulitsky, Pedro A de Alarcon, Victor Weigman, Gur Yaari, Jessica A Panzer, Nir Friedman, John M Maris

Department of Human Biology

Research output: Working paper › Preprint

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, 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.

Original language	English
DOIs	https://doi.org/10.1101/2021.12.14.471886
State	Published - 14 Dec 2021

Bibliographical note

Authors retain copyright and choose from several distribution/reuse options under which to make the article available (CC BY, CC BY-NC, CC BY-ND, CC BY-NC-ND, CC0, or no reuse).

Keywords

cancer-biology

UN SDGs

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

Access to Document

10.1101/2021.12.14.471886

Cite this

Rosenberg, M. I., Greenstein, E., Buchkovich, M., Mikl, M., Peres, A., Santoni-Rugiu, E., Reshef, D., Salovin, A. J., Gibbs, D. L., Irwin, M. S., Naranjo, A., Ulitsky, I., Alarcon, P. A. D., Weigman, V., Yaari, G., Panzer, J. A., Friedman, N., & Maris, J. M. (2021). Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma. https://doi.org/10.1101/2021.12.14.471886

@techreport{564982ff10d645f7a5d64a07aa3e2743,

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, 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.",

keywords = "cancer-biology",

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

note = "Authors retain copyright and choose from several distribution/reuse options under which to make the article available (CC BY, CC BY-NC, CC BY-ND, CC BY-NC-ND, CC0, or no reuse).",

year = "2021",

month = dec,

day = "14",

doi = "10.1101/2021.12.14.471886",

language = "English",

type = "WorkingPaper",

}

TY - UNPB

T1 - Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

AU - Rosenberg, Miriam I

AU - Greenstein, Erez

AU - Buchkovich, Martin

AU - Mikl, Martin

AU - Peres, Ayelet

AU - Santoni-Rugiu, Eric

AU - Reshef, Dan

AU - Salovin, Amy J

AU - Gibbs, David L

AU - Irwin, Meredith S

AU - Naranjo, Arlene

AU - Ulitsky, Igor

AU - Alarcon, Pedro A de

AU - Weigman, Victor

AU - Yaari, Gur

AU - Panzer, Jessica A

AU - Friedman, Nir

AU - Maris, John M

N1 - Authors retain copyright and choose from several distribution/reuse options under which to make the article available (CC BY, CC BY-NC, CC BY-ND, CC BY-NC-ND, CC0, or no reuse).

PY - 2021/12/14

Y1 - 2021/12/14

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, 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.

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, 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.

KW - cancer-biology

U2 - 10.1101/2021.12.14.471886

DO - 10.1101/2021.12.14.471886

M3 - Preprint

BT - Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

ER -

Polyclonal lymphoid expansion drives paraneoplastic autoimmunity in neuroblastoma

Abstract

Bibliographical note

Keywords

UN SDGs

Access to Document

Fingerprint

Cite this