T CELL TRAFFICKING IN PANCREATIC DUCTAL ADENOCARCINOMA

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies with a five-year survival rate of less than 10%. A key challenge in PDAC treatment is its immunologically “cold” tumor microenvironment, characterized by a paucity of infiltrating T cells and a dominance of immunosuppressive factors. Understanding the mechanisms that regulate T cell trafficking into PDAC tumors may provide insights into overcoming these challenges and improve patient outcomes. Thus, we studied the role of T cell infiltration in PDAC and its prognostic implications. Our data, as well as emerging evidence, suggests that enhanced T cell trafficking into PDAC tumors correlates with improved survival and an improved response to immunotherapy. Specifically, our data reveal that PDAC tumors with enhanced T cell tumor infiltration respond more favorably to adoptive T cell immunotherapy than tumors with poor T cell trafficking, resulting in delayed tumor outgrowth and prolonged survival. By leveraging clinical data and immunocompetent genetically engineered mouse models, we found that the pattern recognition receptor, toll-like receptor 2 (TLR2), plays a role in modulating the tumor microenvironment. Our findings suggest that TLR2 activation is implicated in promoting anti-inflammatory immunity by suppressing T cell trafficking to the tumor. Specifically, we found through adoptive T cell transfer, that TLR2 expression on both host cells and adoptively transferred T cells restricted adoptive and endogenous T cell infiltration into tumors. Moreover, genetic ablation and pharmacological inhibition of TLR2 ultimately resulted in decreased tumor growth and a significant extension in overall survival. Taken together, these findings contribute to a deeper understanding of the immune landscape in PDAC and highlight the importance of TLR2 in modulating anti-tumor immunity. They provide a strong rationale for further investigating TLR2-dependent cell-to-cell interactions as well as TLR2-targeted approaches as a means to render PDAC tumors more immunologically responsive, and thus potentially improving therapeutic outcomes.