Pancreatic Cancers with High Grade Tumor Budding Exhibit Hallmarks of Diminished Anti-Tumor Immunity

Abstract

Tumor budding is associated with epithelial-mesenchymal transition and diminished survival in a number of cancer types including pancreatic ductal adenocarcinoma (PDAC). In this study, we dissect the immune landscapes of patients with high grade versus low grade tumor budding to determine the features associated with immune escape and disease progression in pancreatic cancer. We performed immunohistochemistry-based quantification of tumor-infiltrating leukocytes and tumor bud assessment in a cohort of n = 111 PDAC patients in a tissue microarray (TMA) format. Patients were divided based on the ITBCC categories of tumor budding as Low Grade (LG: categories 1 and 2) and High Grade (HG: category 3). Tumor budding numbers and tumor budding grade demonstrated a significant association with diminished overall survival (OS). HG cases exhibit notably reduced densities of stromal (S) and intratumoral (IT) T cells. HG cases also display lower M1 macrophages (S) and increased M2 macrophages (IT). These findings were validated using gene expression data from TCGA. A published tumor budding gene signature demonstrated a significant association with diminished survival in PDAC patients in TCGA. Immune-related gene expression revealed an immunosuppressive TME in PDAC cases with high expression of the budding signature. Our findings highlight a number of immune features that permit an improved understanding of disease progression and EMT in pancreatic cancer.

Tumor Budding Is an Independent Prognostic Factor in Pancreatic Adenocarcinoma and It Positively Correlates with PD-L1 Expression on Tumor Cells

“…Our study demonstrated the positive correlation between high-grade tumor budding and PD-L1 expression on TCs. This finding is supported by a recent study by Sadozai et al, which demonstrated that extensive tumor budding is accompanied by diminished anti-tumor immunity and higher B7-H3 (CD276) expression [ 33 ]. In colorectal cancer, high-grade tumor budding is associated with an up-regulation of negative regulatory immune checkpoints and immune evasion [ 34 ].…”

The role of USP7-YY1 interaction in promoting colorectal cancer growth and metastasis

“…Additionally, we conducted a measurement of YY1 expression levels in patients exhibiting varying TB grades. TB refers to the presence of dedifferentiated tumor cells, which can manifest as solitary cells or small clusters containing up to four cells located at the invasive frontier of diverse cancers [ 28 ]. It is well-documented that TB is linked to EMT and reduced survival rates.…”

Novel Branched-Chain Amino Acid-Catabolism Related Gene Signature for Overall Survival Prediction of Pancreatic Carcinoma

“…In the equation, i represents the grade of staining intensity, which includes no staining ( i = 0), weak ( i = 1), moderate ( i = 2), and strong ( i = 3); p i represents the percentage of labeled tumor cells with the corresponding stating intensity. To quantify immune cell infiltration, positive cells in the tumoral and stromal compartments were enumerated separately and normalized per unit area as cells/mm 2 …”

“…To quantify immune cell infiltration, positive cells in the tumoral and stromal compartments were enumerated separately and normalized per unit area as cells/ mm 2 . 13…”