Abstract Text: Immunotherapy has revolutionized cancer treatment in multiple tumors, but not in pancreatic ductal adenocarcinoma (PDA), one of the lethal malignant solid tumors. Carcinoembryonic antigen-related cell adhesion molecule (CEACAM6) is expressed 10-20-fold higher in PDA than normal pancreatic tissue. In PDA, CEACAM6 immunoinhibitory role remains unexplored. Therefore, we hypothesize that CEACAM6 regulates immune response in PDA by activating NF-B. In-vitro assays using spheroids and two-dimensional cultures of human PDA cells BXPC3 and HPAF treated with monoclonal anti CEACAM6 antibodies significantly restored CD8+ T cell infiltration versus cell lines with untreated cell lines by almost two-folds (p < 0.05). T cell exhaustion markers are significantly lower post-anti-CEACAM6 treatment, accompanied by reduced CD8+ T cell apoptosis 29% vs. 44% in HPAF-II treated vs. untreated, respectively. Amongst various cytokines tested, TNFα+ was significantly higher when co-incubated with T cells. We observed a significant reduction in NF-B signaling in treated versus untreated by proteomic profiler and western blotting. We noticed an alteration in TLR4/MyD88/NF-B axis in PDA cell lines upon activation with LPS, suggesting a potential collaboration between LPS-CEACAM6 in promoting immune evasion in PDA. Therapeutic targeting of CEACAM6 may be a promising strategy to improve PDA treatment and eliminate cell resistance to T cell cytotoxicity.
