Pancreatic adenocarcinomas with mature blood vessels have better overall survival

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is known for its hypovascularity. Bevacizumab, an anti-angiogenic drug, added to standard chemotherapy demonstrated no improvement in outcome for PDAC. Therefore, we hypothesized that increased vascularity may be associated with improved outcomes in PDAC possibly due to better delivery of tumor specific immune cells. To test this hypothesis, PDAC patients were classified into either high or low CD31 expression groups utilizing mRNA expression from RNA-sequence data in The Cancer Genome Atlas (TCGA) pancreatic cancer cohort. High expression of CD31, which indicates presence of more vascular endothelial cells, was associated with significantly better OS (p = 0.002). Multivariate analysis demonstrated that residual tumor (R1, 2; p = 0.026) and CD31 low expression (p = 0.007) were the only independent predictors that negatively impacted OS. Vascular stability as well as immune response related pathways were significantly upregulated in the CD31 high expressing tumors. Furthermore, there were higher proportions of anti-cancer immune cells infiltration, including activated memory CD4+ T cells (p = 0.038), CD8+ T cells (p = 0.027), gamma-delta T cells (p < 0.001) as well as naïve B cells (p = 0.006), whereas lower proportions of regulatory T cell fractions (p = 0.009), which induce an immune tolerant microenvironment, in the CD31 high expressing tumors. These findings imply that stable vessels supply anti-cancer immune cells, which are at least partially responsible for better OS in the CD31 high expressing tumors. In conclusion, CD31 high expressing PDACs have better OS, which may be due to stable vessels that supply anti-cancer immune cells.

Figure 1

CD31 expression and patient survival. (A) OS in PDAC patients in TCGA pancreatic cancer cohort. (B) OS in pancreatic other malignancy patients in TCGA pancreatic cancer cohort. (C) OS in GSE57495 PDAC cohort.

Figure 2

Vascular related gene expression and survival of TCGA PDAC patients. (A) Vascular stability related genes and (B) VEGF related genes. (C) Hypoxia related gene and patient survival.

Figure 3

Heatmap of differently expressed genes between high and low expressing CD31 tumors among TCGA PDAC patients.

Figure 4

Correlation matrix of CD31 and other genes. (A) A list of endothelial cell markers, angiogenesis, hypoxia and immune response related genes, and macrophage and platelet surface markers. (B) Correlation matrix of CD31 and endothelial cell markers, angiogenesis, hypoxia and immune response related genes, and macrophage and platelet cell surface markers.

Figure 5

Vascular stability related pathways are upregulated in CD31 high expressing tumors. (A) The list of significantly upregulated vascular stability related pathways in CD31 high expressing tumors^–. (B) Differential gene expression for “Cell adhesion molecules” pathway is demonstrated with red (high) and green (low) expression.

Figure 6

Immune reaction related pathways are upregulated in CD31 high expressing tumors. (A) The list of significantly upregulated immune response related pathways in CD31 high expressing tumors^–. (B) Differential gene expression for “Chemokine signaling” and (C) “T cell receptor signaling” pathways is demonstrated with red (high) and green (low) expression. (D) Immune cell signaling related gene expression and patient survival in TCGA PDAC patients.

Figure 7

Immune cell component comparisons between CD31 high and low expressing tumors analyzed by CIBERSORT. (A) T cell fraction comparison. (B) B cell fraction comparison.