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Spatial Transcriptome Analysis of B7-H4 in Head and Neck Squamous Cell Carcinoma: A Novel Therapeutic Target for

Yuri Noda1,2, Masao Yagi3, Koji Tsuta4,5

  • 1Department of Pathology and Laboratory Medicine, Kansai Medical University Hospital, 2- 3-1 Shin-machi, Hirakata, Osaka, 573-1191, Japan. nodayuridesu@yahoo.co.jp.

Head and Neck Pathology
|June 30, 2025
PubMed
Abstract

Insights

B7-H4 is a promising target for head and neck squamous cell carcinoma (HNSCC) resistant to immune checkpoint inhibitors (ICIs). Its expression correlates with lower CD8+ T-cell infiltration, suggesting potential for antibody-drug conjugate therapy.

Area of Science:

  • Oncology
  • Immunotherapy
  • Molecular Pathology

Background:

  • Many head and neck squamous cell carcinoma (HNSCC) patients are ineligible for immune checkpoint inhibitors (ICIs) due to low programmed cell death protein-ligand 1 (PD-L1) expression.
  • Investigating alternative therapeutic targets is crucial for improving treatment outcomes in ICI-resistant HNSCC.
  • B7-H4 (VTCN1) has emerged as a potential target in various cancers.

Purpose of the Study:

  • To investigate the therapeutic potential of B7-H4 (VTCN1) in head and neck squamous cell carcinoma (HNSCC).
  • To assess the expression patterns of B7-H4 and its relationship with PD-L1 and immune cell infiltration in HNSCC.
  • To evaluate B7-H4 as a target for antibody-drug conjugate therapy in ICI-resistant HNSCC.

Main Methods:

  • Immunohistochemistry (IHC) was performed on tissue microarrays from HNSCC, squamous intraepithelial neoplasia (SIN), and normal oral mucosa (NOM) samples.
  • Expression levels of B7-H4, PD-L1, CD3, CD4, and CD8 were assessed using tumor cell (TC) score, immune cell score, and combined positive score.
  • Spatial transcriptomics (ST) was used to confirm B7-H4 (VTCN1) and PD-L1 (CD274) expression and distribution in HNSCC, SIN, and NOM.

Main Results:

  • A mutually exclusive expression pattern between B7-H4 and PD-L1 was observed in 55% of HNSCCs.
  • B7-H4 positive tumor cells (TCs) were significantly more frequent in HNSCCs (79%) compared to SINs (10%) and NOMs (2%).
  • B7-H4 expression was significantly correlated with lower CD8+ T-cell infiltration (p=0.009), and CD8A mRNA was downregulated in VTCN1+ areas.

Conclusions:

  • B7-H4 represents a promising target for antibody-drug conjugate therapy in immune checkpoint inhibitor (ICI)-resistant head and neck squamous cell carcinoma (HNSCC).
  • Immunohistochemistry (IHC) combined with tumor cell (TC) scoring provides a reliable method for assessing B7-H4 expression.
  • The observed association of B7-H4 with low CD8+ T-cell infiltration highlights its potential role in immune evasion within the tumor microenvironment.
Keywords:
Antibody–drug conjugateB7-H4Immune checkpoint inhibitorPD-L1Squamous cell carcinoma

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