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Peer-reviewedCC BY-NC-ND 4.0Cancer Immunology, Immunotherapy : CII

Spatial and graded heterogeneity of GD2 expression in neuroblastoma revealed by whole-slide immunohistochemistry

  • Tomoko Fujikawa1
  • Shotaro Inoue1
  • Akihiro Nishimura1
  • Naoko Nakatani1
  • Nobuyuki Yamamoto1
  • Toshiki Hyodo2
  • Makiko Yoshida3
  • Daiichiro Hasegawa4
  • Kandai Nozu1
  • Akihiro Tamura1
4 affiliations
  1. 1Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan
  2. 2Department of Diagnostic Pathology, Kobe University Graduate School of Medicine, Kobe, Japan
  3. 3Department of Pathology, Kobe Children’s Hospital, Kobe, Japan
  4. 4Department of Hematology and Oncology, Kobe Children’s Hospital, Kobe, Japan
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Abstract

Background: Anti-GD2 immunotherapy has improved outcomes in high-risk neuroblastoma; however, therapeutic responses remain heterogeneous. Although GD2 is generally assumed to be uniformly expressed in neuroblastoma, its spatial distribution within clinical tumors has not been systematically characterized. We therefore investigated intratumoral GD2 heterogeneity using whole-slide immunohistochemistry and explored its molecular regulation.

Methods: GD2 expression was evaluated in 45 FFPE neuroblastoma tumors using standardized whole-slide immunohistochemistry and independently assessed by two pathologists. GD2 surface expression was analyzed by flow cytometry in 12 neuroblastoma cell lines. Functional roles of ganglioside biosynthetic enzymes were evaluated using siRNA-mediated knockdown.

Results: Whole-slide immunohistochemistry demonstrated frequent intratumoral GD2 heterogeneity. Fourteen tumors (31%) contained <90% GD2-positive tumor cells, with spatial coexistence of GD2-positive and GD2-negative tumor cell populations within the same lesion. One tumor showed minimal GD2 expression with only rare GD2-positive tumor cells. Consistent with these tissue-level findings, GD2 surface expression varied widely across neuroblastoma cell lines and within clonally related subpopulations. Among ganglioside biosynthetic enzymes, ST8SIA1 showed the strongest association with GD2 expression, and siRNA-mediated suppression of ST8SIA1 significantly reduced GD2 surface expression.

Conclusions: GD2 expression in neuroblastoma is frequently heterogeneous, with spatial coexistence of GD2-positive and GD2-negative tumor cells within individual tumors. These findings suggest that GD2 exists along a biological continuum rather than a uniform phenotype and provide a framework for future studies investigating the biological and clinical significance of GD2 heterogeneity. (228 words).

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00262-026-04508-7.

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Cite

BibTeXRIS
BibTeX
@article{fujikawa2026spatial,
  title = {{Spatial and graded heterogeneity of GD2 expression in neuroblastoma revealed by whole-slide immunohistochemistry}},
  author = {Tomoko Fujikawa and Shotaro Inoue and Akihiro Nishimura and Naoko Nakatani and Nobuyuki Yamamoto and Toshiki Hyodo and Makiko Yoshida and Daiichiro Hasegawa and Kandai Nozu and Akihiro Tamura},
  journal = {Cancer Immunology, Immunotherapy : CII},
  year = {2026},
  month = jul,
  doi = {10.1007/s00262-026-04508-7},
  url = {https://doi.org/10.1007/s00262-026-04508-7},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Spatial and graded heterogeneity of GD2 expression in neuroblastoma revealed by whole-slide immunohistochemistry
AU  - Tomoko Fujikawa
AU  - Shotaro Inoue
AU  - Akihiro Nishimura
AU  - Naoko Nakatani
AU  - Nobuyuki Yamamoto
AU  - Toshiki Hyodo
AU  - Makiko Yoshida
AU  - Daiichiro Hasegawa
AU  - Kandai Nozu
AU  - Akihiro Tamura
PY  - 2026
DA  - 2026/07/29
JO  - Cancer Immunology, Immunotherapy : CII
DO  - 10.1007/s00262-026-04508-7
UR  - https://doi.org/10.1007/s00262-026-04508-7
AB  - Background: Anti-GD2 immunotherapy has improved outcomes in high-risk neuroblastoma; however, therapeutic responses remain heterogeneous. Although GD2 is generally assumed to be uniformly expressed in neuroblastoma, its spatial distribution within clinical tumors has not been systematically characterized. We therefore investigated intratumoral GD2 heterogeneity using whole-slide immunohistochemistry and explored its molecular regulation.  Methods: GD2 expression was evaluated in 45 FFPE neuroblastoma tumors using standardized whole-slide immunohistochemistry and independently assessed by two pathologists. GD2 surface expression was analyzed by flow cytometry in 12 neuroblastoma cell lines. Functional roles of ganglioside biosynthetic enzymes were evaluated using siRNA-mediated knockdown.  Results: Whole-slide immunohistochemistry demonstrated frequent intratumoral GD2 heterogeneity. Fourteen tumors (31%) contained <90% GD2-positive tumor cells, with spatial coexistence of GD2-positive and GD2-negative tumor cell populations within the same lesion. One tumor showed minimal GD2 expression with only rare GD2-positive tumor cells. Consistent with these tissue-level findings, GD2 surface expression varied widely across neuroblastoma cell lines and within clonally related subpopulations. Among ganglioside biosynthetic enzymes, ST8SIA1 showed the strongest association with GD2 expression, and siRNA-mediated suppression of ST8SIA1 significantly reduced GD2 surface expression.  Conclusions: GD2 expression in neuroblastoma is frequently heterogeneous, with spatial coexistence of GD2-positive and GD2-negative tumor cells within individual tumors. These findings suggest that GD2 exists along a biological continuum rather than a uniform phenotype and provide a framework for future studies investigating the biological and clinical significance of GD2 heterogeneity. (228 words).  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00262-026-04508-7.
SN  - 0340-7004
SN  - 1432-0851
ER  -