Ghahremanifard Parisa, An Jinsu, Chanda Ayan, Chan Angela M Y, Nakoneshny Steven C, Matthews T Wayne, Chandarana Shamir P, Hart Robert D, Hyrcza Martin D, Dort Joseph C, Bonni Shirin, Bose Pinaki
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Cancers (Basel). 2025 Sep 4;17(17):2905. doi: 10.3390/cancers17172905.
The SUMO E3 ligase PIAS1 (Protein Inhibitor of Activated STAT1) regulates pathways such as TGFβ signaling and has been implicated in multiple cancers. However, its role in the tumor microenvironment (TME), particularly in non-malignant stromal and immune cells, remains poorly understood. This study aimed to characterize the expression and functional relevance of PIAS1 within the TME of oral squamous cell carcinoma (OSCC).
PIAS1 protein expression was assessed via immunohistochemistry (IHC) on OSCC tissue microarrays. Single-cell RNA-sequencing (scRNA-seq) datasets from OSCC tumors and normal tissues were analyzed to map cell-type-specific PIAS1 expression. Downstream effects were evaluated using differential gene expression, Ingenuity Pathway Analysis (IPA), gene set enrichment analysis (GSEA), and cell-cell communication inference.
IHC analysis revealed that higher stromal PIAS1 levels correlated with improved survival. scRNA-seq analysis showed an increase in the proportion of PIAS1-expressing cells across most stromal and immune cell populations within OSCC-derived tumors compared to their counterparts in adjacent normal tissue. However, when comparing PIAS1-positive cells, expression levels were significantly reduced in cancer cells, CAFs, TAMs, T cells, and endothelial cells within the TME. PIAS1-positive CAFs, TAMs, and T cells exhibited activation of apoptotic and tumor-suppressive pathways, while PIAS1-negative counterparts showed enrichment of immunosuppressive signaling and immune checkpoint expression. Cell-cell communication analyses indicated that PIAS1 fosters an immune-activated TME by promoting pro-inflammatory signaling, M1-like TAM polarization, and T cell activation.
PIAS1 expression in stromal and immune cells is associated with tumor-suppressive reprogramming of the OSCC microenvironment. These findings position PIAS1 as a potential modulator of anti-tumor immunity and candidate target for therapeutic intervention.
小泛素样修饰物E3连接酶PIAS1（信号转导和转录激活因子1的蛋白抑制剂）可调节诸如转化生长因子β信号传导等通路，并与多种癌症相关。然而，其在肿瘤微环境（TME）中的作用，尤其是在非恶性基质细胞和免疫细胞中的作用，仍知之甚少。本研究旨在明确PIAS1在口腔鳞状细胞癌（OSCC）肿瘤微环境中的表达及其功能相关性。
通过免疫组织化学（IHC）对OSCC组织芯片进行PIAS1蛋白表达评估。分析来自OSCC肿瘤和正常组织的单细胞RNA测序（scRNA-seq）数据集，以绘制细胞类型特异性PIAS1表达图谱。使用差异基因表达、 Ingenuity通路分析（IPA）、基因集富集分析（GSEA）和细胞间通讯推断来评估下游效应。
IHC分析显示，较高的基质PIAS1水平与生存率提高相关。scRNA-seq分析表明，与相邻正常组织相比，OSCC衍生肿瘤中大多数基质和免疫细胞群体中表达PIAS1的细胞比例增加。然而，在比较PIAS1阳性细胞时，肿瘤微环境中的癌细胞（CAFs）、肿瘤相关巨噬细胞（TAMs）、T细胞和内皮细胞中的表达水平显著降低。PIAS1阳性的CAFs、TAMs和T细胞表现出凋亡和肿瘤抑制通路的激活，而PIAS1阴性的对应细胞则表现出免疫抑制信号和免疫检查点表达的富集。细胞间通讯分析表明，PIAS1通过促进促炎信号传导、M1样TAM极化和T细胞激活，促进免疫激活的肿瘤微环境。
基质细胞和免疫细胞中的PIAS1表达与OSCC微环境的肿瘤抑制重编程相关。这些发现表明PIAS1是抗肿瘤免疫的潜在调节因子和治疗干预的候选靶点。
