Plectin promotes an aggressive phenotype and represses cytotoxic T cell activity in pancreatic cancer
TL;DR
Plectin is identified as a biomarker of aggressive disease in PDAC, with high plectin expression associated with decreased T cell infiltration, and anti-CSP treatment reinstates antitumor immunity and decreases tumor volume in vivo.
Abstract
Background Pancreatic adenocarcinoma (PDAC) is an abysmal disease with poor clinical outcomes, largely due to limited life-extending treatments. Notably, PDAC displays a T cell-suppressive tumor microenvironment, and the underlying molecular mechanisms that lead to this phenotype remain poorly understood. Methods Utilizing the TCGA-PAAD dataset, tumor samples were separated by PLEC expression to evaluate patient survival, and pathway analyses associated with increased tumorigenesis. Evaluation of immune infiltration and subsequent immune deconvolution was performed using tidyestimate and CIBERSORTx R packages and immunohistochemistry (IHC) from human PDAC samples was performed to analyze PLEC expression and immune cell infiltration. Single-cell RNA-seq (scRNA-seq) analysis from 229 PDAC patients was analyzed to investigate signaling dynamics and immune cell infiltration in PLECHigh patients. Functional validation was provided using a monoclonal antibody (mAb) against cell surface plectin (CSP) in two murine PDAC models to examine changes in tumor growth and immune cell subset abundance. Results Our studies revealed that high plectin expression results in an overall worse survival associated with activation of pro-tumorigenic pathways and decreased anti-tumor immune signature in PDAC patients. Analysis via GSEA indicates PLECHigh patients display an aggressive phenotype and suppressed pro-inflammatory signaling pathways. Immune ESTIMATE scores were significantly decreased in PLECHigh patients, and IHC and scRNA-seq analysis revealed that PLECHigh tumors display a decrease in anti-tumor CD8+ T cells. In vivo analyses using an anti-CSP mAb revealed a reduction in tumor growth kinetics compared to IgG control corresponding with a significant increase in proliferating and activated cytotoxic CD8+ T cells. Anti-CSP-mediated tumor suppression was inhibited when CD8+ T cells were depleted, indicating that anti-CSP treatment is contingent on cytotoxic T cell functionality. Discussion Our findings identify plectin as a biomarker of aggressive disease in PDAC, with high plectin expression associated with decreased T cell infiltration, and anti-CSP treatment reinstates antitumor immunity and decreases tumor volume in vivo. These findings suggest that plectin is a novel therapeutic target with the potential to enhance immune responses in PDAC and improve patient outcomes.