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

Head and neck pathology Pub Date : 2025-06-30 DOI:10.1007/s12105-025-01815-w

Yuri Noda, Masao Yagi, Koji Tsuta

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Abstract

Purpose: A significant proportion of patients with head and neck squamous cell carcinoma (HNSCC) are ineligible for immune checkpoint inhibitors (ICIs) because of low programmed cell death protein-ligand 1 (PD-L1) expression. The therapeutic potential of B7-H4 (VTCN1) was investigated using immunohistochemistry (IHC) and spatial transcriptomics (ST).

Methods: IHC analysis of B7-H4, PD-L1, CD3, CD4, and CD8 was performed using a tissue microarray [94 HNSCC, 94 adjacent squamous intraepithelial neoplasia (SIN), and 69 adjacent normal oral mucosa (NOM) samples]. B7-H4 and PD-L1 expression levels were assessed using tumor cell score (TC; positive, TC > 1%), immune cell score, and combined positive score. ST was performed on six HNSCCs with paired SINs and NOMs to confirm the expression and distribution of B7-H4 (CTVN1), PD-L1 (CD274), CD4 (DC4A), and CD8 (CD8).

Results: In HNSCCs, TCs revealed a mutually exclusive B7-H4/PD-L1 expression pattern in 55% of samples (p < 0.05). B7-H4 positive TCs were more frequent in HNSCCs (79%) than in SINs (10%) and NOMs (2%). ST analysis confirmed mutually exclusive VTCN1/CD274 upregulation in 83% of samples (n = 6) and demonstrated co-localization of B7-H4 protein and VTCN1 in IHC-positive areas. B7-H4 was significantly correlated with low-CD8⁺ T-cell infiltration (n = 94, p = 0.009), and CD8A mRNA was down-regulated in the VTCN1⁺ area compared with that in the VTCN1⁺ area.

Conclusion: B7-H4 is a promising antibody-drug conjugate target in ICI-resistant HNSCC. IHC combined with TCs enabled the reliable assessment of B7-H4, given its co-localization with VTCN1 in IHC-positive areas and association with low-CD8⁺ T-cells.

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B7-H4在头颈部鳞状细胞癌中的空间转录组分析：抗免疫检查点抑制剂的新治疗靶点

目的：相当比例的头颈部鳞状细胞癌（HNSCC）患者由于程序性细胞死亡蛋白-配体1 （PD-L1）表达低而不适合免疫检查点抑制剂（ICIs）。利用免疫组织化学（IHC）和空间转录组学（ST）研究B7-H4 （VTCN1）的治疗潜力。方法：采用组织芯片对94例HNSCC、94例相邻鳞状上皮内瘤变（SIN）和69例相邻正常口腔黏膜（NOM）样本进行免疫组化分析，检测B7-H4、PD-L1、CD3、CD4和CD8。B7-H4和PD-L1表达水平采用肿瘤细胞评分(TC；阳性，TC(1%)，免疫细胞评分，和综合阳性评分。我们对6例配对SINs和NOMs的HNSCCs进行ST检测，以确定B7-H4 （CTVN1）、PD-L1 （CD274）、CD4 （DC4A）和CD8 （CD8）的表达和分布。结果：在HNSCCs中，55%的样本TCs显示B7-H4/PD-L1相互排斥的表达模式（p + t细胞浸润（n = 94, p = 0.009））， CD8A mRNA在VTCN1+区域较VTCN1+区域下调。结论：B7-H4是一种很有前景的抗i -耐药HNSCC抗体-药物结合靶点。考虑到B7-H4与VTCN1在IHC阳性区域共定位并与低cd8 + t细胞相关，IHC联合tc能够可靠地评估B7-H4。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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Head and neck pathology

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