Pearson, J.; Yang, J.-I.; Krivitsky, S.; Kelley, Z.; Fearon, D. T.

Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive cancer known for its ability to evade immune surveillance, primarily through mechanisms that prevent T cell infiltration. While the coating of cancer cells with the chemokine, CXCL12, is required for the exclusion of T cells, the precise molecular mechanisms behind the failure of T cell migration into the tumor remain unclear. In this study, we identify a potential mechanism by demonstrating that crosslinking CXCR4 is associated with decreased motility of T cells secondary to their adhesion to fibronectin. Using human lymphoblastoid T cells and primary human T cells, we show that polymeric CXCL12-induced crosslinked CXCR4 triggers the non-G i-dependent pathway of tyrosine phosphorylation of FAK-related proline-rich tyrosine kinase 2 (PTK2B) in T cells. This response is necessary for the decreased motility and increased adhesion of T cells. We also find that the downstream cellular reactions of this pathway is secondary to CXCR4-crosslinking and require the integrin subunit, 4, and TNF stimulation of TNFRSF1B. These findings provide insights into the mechanisms mediating the exclusion of T cells from nests of PDA cells and further support therapeutic strategies aimed at blocking the interaction of CXCR4 on T cells with the CXCL12-coating of PDA cells.