Combined sialic acid and HDAC inhibitor treatment upregulates the neuroblastoma antigen GD2

Renske J E van den Bijgaart; Michiel Kroesen; Melissa Wassink; Ingrid C Brok; Esther D Kers-Rebel; Louis Boon; Torben Heise; Monique van Scherpenzeel; Dirk J Lefeber; Thomas J Boltje; Martijn H den Brok; Peter M Hoogerbrugge; Christian Büll; Gosse J Adema

doi:10.1074/jbc.ra118.002763

Combined sialic acid and HDAC inhibitor treatment upregulates the neuroblastoma antigen GD2

Renske J E van den Bijgaart, Michiel Kroesen, Melissa Wassink, Ingrid C Brok, Esther D Kers-Rebel, Louis Boon, Torben Heise, Monique van Scherpenzeel, Dirk J Lefeber, Thomas J Boltje, Martijn H den Brok, Peter M Hoogerbrugge, Christian Büll, Gosse J Adema

Glycomics Program

7 Citations (Scopus)

Abstract

Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is only sparsely expressed on healthy tissue. GD2 is a primary target for the development of immunotherapy for neuroblastoma. Immunotherapy with monoclonal anti-GD2 antibodies has proven safety and efficacy in clinical trials and is included in the standard treatment for children with high-risk neuroblastoma. Strategies to modulate GD2 expression in neuroblastoma could further improve anti-GD2–targeted immunotherapy. Here, we report that the cellular sialylation pathway, as well as epigenetic reprogramming, strongly modulates GD2 expression in human and mouse neuroblastoma cell lines. Recognition of GD2 by the 14G2a antibody is sialic acid– dependent and was blocked with the fluorinated sialic acid mimetic Ac₅3F_axNeu5Ac. Interestingly, sialic acid supplementation using a cell-permeable sialic acid analogue (Ac₅Neu5Ac) boosted GD2 expression without or with minor alterations in overall cell surface sialylation. Furthermore, sialic acid supplementation with Ac₅Neu5Ac combined with various histone deacetylase (HDAC) inhibitors, including vorinostat, enhanced GD2 expression in neuroblastoma cells beyond their individual effects. Mechanistic studies revealed that Ac₅Neu5Ac supplementation increased intracellular CMP–Neu5Ac concentrations, thereby providing higher substrate levels for sialyltransferases. Furthermore, HDAC inhibitor treatment increased mRNA expression of the sialyltransferases GM3 synthase (ST3GAL5) and GD3 synthase (ST8SIA1), both of which are involved in GD2 biosynthesis. Our findings reveal that sialic acid analogues and HDAC inhibitors enhance GD2 expression and could potentially be employed to boost anti-GD2 targeted immunotherapy in neuroblastoma patients.

Original language	English
Journal	The Journal of Biological Chemistry
ISSN	0021-9258
DOIs	https://doi.org/10.1074/jbc.ra118.002763
Publication status	Published - 22 Mar 2019

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van den Bijgaart, R. J. E., Kroesen, M., Wassink, M., Brok, I. C., Kers-Rebel, E. D., Boon, L., Heise, T., van Scherpenzeel, M., Lefeber, D. J., Boltje, T. J., den Brok, M. H., Hoogerbrugge, P. M., Büll, C., & Adema, G. J. (2019). Combined sialic acid and HDAC inhibitor treatment upregulates the neuroblastoma antigen GD2. The Journal of Biological Chemistry. https://doi.org/10.1074/jbc.ra118.002763

@article{c8cc73e3942e44b4b2bff47836a58d84,

title = "Combined sialic acid and HDAC inhibitor treatment upregulates the neuroblastoma antigen GD2",

abstract = "Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is only sparsely expressed on healthy tissue. GD2 is a primary target for the development of immunotherapy for neuroblastoma. Immunotherapy with monoclonal anti-GD2 antibodies has proven safety and efficacy in clinical trials and is included in the standard treatment for children with high-risk neuroblastoma. Strategies to modulate GD2 expression in neuroblastoma could further improve anti-GD2–targeted immunotherapy. Here, we report that the cellular sialylation pathway, as well as epigenetic reprogramming, strongly modulates GD2 expression in human and mouse neuroblastoma cell lines. Recognition of GD2 by the 14G2a antibody is sialic acid– dependent and was blocked with the fluorinated sialic acid mimetic Ac53FaxNeu5Ac. Interestingly, sialic acid supplementation using a cell-permeable sialic acid analogue (Ac5Neu5Ac) boosted GD2 expression without or with minor alterations in overall cell surface sialylation. Furthermore, sialic acid supplementation with Ac5Neu5Ac combined with various histone deacetylase (HDAC) inhibitors, including vorinostat, enhanced GD2 expression in neuroblastoma cells beyond their individual effects. Mechanistic studies revealed that Ac5Neu5Ac supplementation increased intracellular CMP–Neu5Ac concentrations, thereby providing higher substrate levels for sialyltransferases. Furthermore, HDAC inhibitor treatment increased mRNA expression of the sialyltransferases GM3 synthase (ST3GAL5) and GD3 synthase (ST8SIA1), both of which are involved in GD2 biosynthesis. Our findings reveal that sialic acid analogues and HDAC inhibitors enhance GD2 expression and could potentially be employed to boost anti-GD2 targeted immunotherapy in neuroblastoma patients.",

author = "{van den Bijgaart}, {Renske J E} and Michiel Kroesen and Melissa Wassink and Brok, {Ingrid C} and Kers-Rebel, {Esther D} and Louis Boon and Torben Heise and {van Scherpenzeel}, Monique and Lefeber, {Dirk J} and Boltje, {Thomas J} and {den Brok}, {Martijn H} and Hoogerbrugge, {Peter M} and Christian B{\"u}ll and Adema, {Gosse J}",

note = "Published under license by The American Society for Biochemistry and Molecular Biology, Inc.",

year = "2019",

month = mar,

day = "22",

doi = "10.1074/jbc.ra118.002763",

language = "English",

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issn = "0021-9258",

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TY - JOUR

T1 - Combined sialic acid and HDAC inhibitor treatment upregulates the neuroblastoma antigen GD2

AU - van den Bijgaart, Renske J E

AU - Kroesen, Michiel

AU - Wassink, Melissa

AU - Brok, Ingrid C

AU - Kers-Rebel, Esther D

AU - Boon, Louis

AU - Heise, Torben

AU - van Scherpenzeel, Monique

AU - Lefeber, Dirk J

AU - Boltje, Thomas J

AU - den Brok, Martijn H

AU - Hoogerbrugge, Peter M

AU - Büll, Christian

AU - Adema, Gosse J

N1 - Published under license by The American Society for Biochemistry and Molecular Biology, Inc.

PY - 2019/3/22

Y1 - 2019/3/22

N2 - Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is only sparsely expressed on healthy tissue. GD2 is a primary target for the development of immunotherapy for neuroblastoma. Immunotherapy with monoclonal anti-GD2 antibodies has proven safety and efficacy in clinical trials and is included in the standard treatment for children with high-risk neuroblastoma. Strategies to modulate GD2 expression in neuroblastoma could further improve anti-GD2–targeted immunotherapy. Here, we report that the cellular sialylation pathway, as well as epigenetic reprogramming, strongly modulates GD2 expression in human and mouse neuroblastoma cell lines. Recognition of GD2 by the 14G2a antibody is sialic acid– dependent and was blocked with the fluorinated sialic acid mimetic Ac53FaxNeu5Ac. Interestingly, sialic acid supplementation using a cell-permeable sialic acid analogue (Ac5Neu5Ac) boosted GD2 expression without or with minor alterations in overall cell surface sialylation. Furthermore, sialic acid supplementation with Ac5Neu5Ac combined with various histone deacetylase (HDAC) inhibitors, including vorinostat, enhanced GD2 expression in neuroblastoma cells beyond their individual effects. Mechanistic studies revealed that Ac5Neu5Ac supplementation increased intracellular CMP–Neu5Ac concentrations, thereby providing higher substrate levels for sialyltransferases. Furthermore, HDAC inhibitor treatment increased mRNA expression of the sialyltransferases GM3 synthase (ST3GAL5) and GD3 synthase (ST8SIA1), both of which are involved in GD2 biosynthesis. Our findings reveal that sialic acid analogues and HDAC inhibitors enhance GD2 expression and could potentially be employed to boost anti-GD2 targeted immunotherapy in neuroblastoma patients.

AB - Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is only sparsely expressed on healthy tissue. GD2 is a primary target for the development of immunotherapy for neuroblastoma. Immunotherapy with monoclonal anti-GD2 antibodies has proven safety and efficacy in clinical trials and is included in the standard treatment for children with high-risk neuroblastoma. Strategies to modulate GD2 expression in neuroblastoma could further improve anti-GD2–targeted immunotherapy. Here, we report that the cellular sialylation pathway, as well as epigenetic reprogramming, strongly modulates GD2 expression in human and mouse neuroblastoma cell lines. Recognition of GD2 by the 14G2a antibody is sialic acid– dependent and was blocked with the fluorinated sialic acid mimetic Ac53FaxNeu5Ac. Interestingly, sialic acid supplementation using a cell-permeable sialic acid analogue (Ac5Neu5Ac) boosted GD2 expression without or with minor alterations in overall cell surface sialylation. Furthermore, sialic acid supplementation with Ac5Neu5Ac combined with various histone deacetylase (HDAC) inhibitors, including vorinostat, enhanced GD2 expression in neuroblastoma cells beyond their individual effects. Mechanistic studies revealed that Ac5Neu5Ac supplementation increased intracellular CMP–Neu5Ac concentrations, thereby providing higher substrate levels for sialyltransferases. Furthermore, HDAC inhibitor treatment increased mRNA expression of the sialyltransferases GM3 synthase (ST3GAL5) and GD3 synthase (ST8SIA1), both of which are involved in GD2 biosynthesis. Our findings reveal that sialic acid analogues and HDAC inhibitors enhance GD2 expression and could potentially be employed to boost anti-GD2 targeted immunotherapy in neuroblastoma patients.

U2 - 10.1074/jbc.ra118.002763

DO - 10.1074/jbc.ra118.002763

M3 - Journal article

C2 - 30670592

SN - 0021-9258

JO - The Journal of Biological Chemistry

JF - The Journal of Biological Chemistry

ER -

Combined sialic acid and HDAC inhibitor treatment upregulates the neuroblastoma antigen GD2

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