High Mesothelin Expression is Associated with Reduced T Cell Infiltration in Pancreatic Cancer

This study reveals the association between MSLN expression and the pancreatic cancer immune microenvironment, suggesting MSLN's role in immune regulation may impact immunotherapy efficacy. It provides reference for optimizing future MSLN-targeted immunotherapies.

 

Literature Overview
The article titled 'High mesothelin expression is associated with low cytotoxic T cell infiltration in pancreatic cancer' published in Frontiers in Immunology reviews MSLN expression patterns in pancreatic cancer and their correlations with immune microenvironment and clinical prognosis. The study identifies that high MSLN expression correlates with reduced T cell infiltration while potentially improving recurrence-free survival, offering new insights for pancreatic cancer immunotherapy strategies.

Background Knowledge
Pancreatic ductal adenocarcinoma (PDAC) represents the most lethal and prevalent subtype (>90% of pancreatic malignancies). PDAC's highly immunosuppressive tumor microenvironment (TME) contributes to poor immunotherapy response rates. Mesothelin (MSLN), a cell surface glycoprotein overexpressed in PDAC, serves as a potential immunotherapy target. Despite multiple MSLN-targeting therapies in clinical trials, limited efficacy suggests unclear biological functions. Immune microenvironment characteristics, particularly T cell infiltration levels, critically determine immunotherapy outcomes. This study systematically evaluates MSLN expression-immune cell infiltration relationships through tissue microarrays, transcriptomic, and single-cell sequencing analyses to provide theoretical support for MSLN-targeted immunotherapies.

 

 

Research Methods and Experiments
The research team conducted immunohistochemical (IHC) analysis of MSLN expression in 74 PDAC patients using tissue microarrays (TMAs) combined with H-score quantification. High MSLN expression was defined as H-score≥62. Public transcriptomic datasets (bulk RNA-seq and scRNA-seq) were employed to analyze MSLN-immune microenvironment associations, with IHC validation of immune cell markers including CD3, CD8, and CD68.

Key Conclusions and Perspectives

• High MSLN expression (H-score≥62) correlates with improved recurrence-free survival (RFS) in PDAC patients (p=0.021).
• MSLN overexpression associates with immunosuppressive microenvironment characterized by reduced immune activation and decreased CD8+ T cell infiltration.
• Single-cell sequencing reveals MSLN primarily expresses in malignant ductal cells, with significantly lower CD8+ T cell proportions in high MSLN groups (5.5% vs 9.5%).
• IHC validation shows trends of inverse correlation between high MSLN expression and low CD8/CD3 scores, though statistical significance not achieved likely due to limited sample size.
• MSLN correlates with PD-L1 or M2 macrophage markers but shows no significant differences in CD8+ T cell exhaustion phenotypes, suggesting MSLN mainly affects T cell infiltration rather than exhaustion.

Research Significance and Prospects
This study represents the first systematic analysis of MSLN-immune microenvironment relationships in an Australian PDAC cohort. Findings indicate MSLN not only serves as a potential therapeutic target but also functions as a biomarker influencing PDAC immunotherapy outcomes. Future research should validate MSLN-immune checkpoint inhibitor combinations in larger cohorts and explore mechanisms underlying MSLN's impact on distinct immune subtypes.

 

 

Conclusion
This study systematically evaluates MSLN expression and its correlations with clinical parameters and immune microenvironment in Australian PDAC cohorts. High MSLN expression associates with decreased CD8+ T cell infiltration and immunosuppressive environment, suggesting potential roles in PDAC immune escape mechanisms. While high MSLN expression correlates with prolonged recurrence-free survival, underlying mechanisms require further investigation. The findings provide new theoretical foundations for MSLN-targeted immunotherapies and recommend personalized treatment strategies incorporating immune microenvironment characteristics.

 

Oliver Liang, Amy L White, Timothy Fielder, Ulf Schmitz, and Dannel Yeo. High mesothelin expression is associated with low cytotoxic T cell infiltration in pancreatic cancer. Frontiers in Immunology.