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

SIMPLE SUMMARY: Pancreatic cancer, in its most common manifestation pancreatic ductal adenocarcinoma (PDAC), is a uniquely lethal disease with very limited treatment options and few prognostic biomarkers. Tumor budding is a proven independent, adverse prognostic factor in many tumor types including PDAC. Tumor buds can be detected histologically as single cancer cells or clusters of up to four cancer cells at the tumor invasive front. Tumor budding is biologically correlated to the induction of epithelial-mesenchymal transitions (EMT) and disease progression. In this study, we sought to investigate the immunological composition of tumors with high levels of tumor budding. We show that PDAC cases with a high grade of tumor budding display notably diminished anti-tumor immunity. These findings were further validated by gene expression analysis of PDAC cases from The Cancer Genome Atlas (TCGA). Our results provide insight on the immune escape mechanisms of tumor cells undergoing EMT. This offers the potential of designing novel treatments combining immunotherapies with EMT-targeted drugs. 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.