Abstract 5361: Aberrant glycosylation in mPDAC is associated with increased epithelial-mesenchymal transition and recruitment of immunosuppressive cells

Abstract

Abstract The tumor-associated glycan Tn antigen (GalNAc-α-O-Ser/Thr) is associated with poor prognosis in various solid tumors. However, the mechanisms that Tn antigen promotes tumorigenesis are incompletely understood. Here, we generated Tn antigen-expressing murine pancreatic ductal adenocarcinoma (mPDAC) tumor cell lines through CRISPR/Cas9-mediated knockout of the C1galt1c1 gene. Tn antigen expressing mPDAC cell lines exhibited increased in vitro proliferation and migration compared to parental controls. RNA sequencing revealed that loss of C1galt1c1 in mPDAC cells correlated with increased expression of genes associated with epithelial-mesenchymal transition, myeloid recruitment, and extracellular matrix deposition. Consequently, knock-down of elevated genes using CRISPR interference dampened in vitro cell proliferation of C1galt1c1 knockout mPDAC cells to the growth rate of parental controls. Additionally, C1galt1c1 knockout mPDAC cells implanted into mice led to accelerated tumor growth and increased tumor infiltration of myeloid-derived suppressor cells and neutrophils as determined by flow cytometry and scRNAseq. Interestingly, surface expression of a binding partner of Tn antigen, macrophage galactose-type lectin 2 (Mgl2), was altered in the immune infiltrate of C1galt1c1 knockout tumors suggesting a role for the Mgl2-Tn interaction in tumor progression. Mgl2-deficient mice exhibit increased T effector cells in the draining lymph nodes of tumors highlighting a potential mechanism for promoting the influx of immune cells in ordinarily cold tumors. Together, our data indicate that truncated O-glycans expressed commonly on tumor cells promotes tumorigenesis through creating an immunosuppressive microenvironment in mPDAC. Citation Format: Shawna Brookens, David Degaramo, Kiesha Wilson, Wilder Condori Obregon, Prakash Nagarkatti, Mitzi Nagarkatti, Avery Posey Jr.. Aberrant glycosylation in mPDAC is associated with increased epithelial-mesenchymal transition and recruitment of immunosuppressive cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5361.