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PIAS1 Shapes a Tumor-Suppressive Microenvironment by Suppressing Immune Evasion in Oral Squamous Cell Carcinoma
Parisa Ghahremanifard1,2, Jinsu An1,2, Ayan Chanda1,2
1Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
Background:
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).
Methods:
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.
Results:
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.
Conclusions:
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.
Insights
Protein Inhibitor of Activated STAT1 (PIAS1) in oral cancer stroma promotes anti-tumor immunity. PIAS1 expression in stromal and immune cells reprograms the tumor microenvironment, suggesting PIAS1 as a therapeutic target.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Protein Inhibitor of Activated STAT1 (PIAS1) is a SUMO E3 ligase involved in cancer pathways.
- Its role in the tumor microenvironment (TME), especially in non-malignant cells, is not well understood.
- This study investigates PIAS1 in the TME of oral squamous cell carcinoma (OSCC).
Purpose of the Study:
- To characterize PIAS1 expression in the OSCC tumor microenvironment.
- To determine the functional relevance of PIAS1 in stromal and immune cells.
- To explore PIAS1's impact on anti-tumor immunity and therapeutic potential.
Main Methods:
- Immunohistochemistry (IHC) to assess PIAS1 protein levels in OSCC tissues.
- Single-cell RNA sequencing (scRNA-seq) to map cell-type-specific PIAS1 expression.
- Bioinformatic analyses including differential gene expression, IPA, GSEA, and cell-cell communication.
Main Results:
- Higher stromal PIAS1 correlated with improved patient survival.
- PIAS1 expression increased in most stromal/immune cells but decreased in cancer cells within the TME.
- PIAS1-positive immune cells showed tumor-suppressive pathways, unlike PIAS1-negative cells with immunosuppressive signaling.
Conclusions:
- PIAS1 in stromal and immune cells drives tumor-suppressive reprogramming of the OSCC microenvironment.
- PIAS1 influences anti-tumor immunity by promoting pro-inflammatory signaling and immune cell activation.
- PIAS1 is a potential therapeutic target for modulating anti-tumor immunity in OSCC.
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