Noda Yuri, Yagi Masao, Tsuta Koji
Department of Pathology and Laboratory Medicine, Kansai Medical University Hospital, 2- 3-1 Shin-machi, Hirakata, Osaka, 573-1191, Japan.
Department of Pathology, Kansai Medical University, 2-5-1 Shin-machi, Hirakata, Osaka, 573-1010, Japan.
Head Neck Pathol. 2025 Jun 30;19(1):78. doi: 10.1007/s12105-025-01815-w.
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).
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).
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.
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.
由于程序性细胞死亡蛋白配体1（PD-L1）表达水平低，相当一部分头颈部鳞状细胞癌（HNSCC）患者不符合免疫检查点抑制剂（ICI）治疗条件。本研究采用免疫组织化学（IHC）和空间转录组学（ST）技术探讨B7-H4（VTCN1）的治疗潜力。
使用组织芯片[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]对B7-H4、PD-L1、CD3、CD4和CD8进行IHC分析。使用肿瘤细胞评分（TC；阳性，TC>1%）、免疫细胞评分和综合阳性评分评估B7-H4和PD-L1的表达水平。对6例伴有配对SIN和NOM的HNSCC进行ST分析，以确认B7-H4（CTVN1）、PD-L1（CD274）、CD4（DC4A）和CD8（CD8）的表达和分布。
在HNSCC中，55%的样本TC显示出B7-H4/PD-L1相互排斥的表达模式（p<0.05）。HNSCC中B7-H4阳性TC的频率（79%）高于SIN（10%）和NOM（2%）。ST分析证实83%的样本（n=6）中VTCN1/CD274相互排斥上调，并在IHC阳性区域显示B7-H4蛋白与VTCN1共定位。B7-H4与低CD8 T细胞浸润显著相关（n=94，p=0.009），与VTCN1区域相比，VTCN1区域CD8A mRNA下调。
B7-H4是ICI耐药HNSCC中有前景的抗体药物偶联物靶点。鉴于B7-H4在IHC阳性区域与VTCN1共定位且与低CD8 T细胞相关，IHC结合TC能够可靠地评估B7-H4。
