MregDCs preferentially associate with regulatory T cells in the pancreatic tumor microenvironment

Two major, contradictory forces act simultaneously on immune cells in the tumor microenvironment (TME): one enhances the immune response following the identification of danger, while the other protects the tumor by imposing an immunosuppressive environment. The interactions between immune cells in the TME are therefore critical for the ability to mount an effective immune response and for the outcome of related therapies. Here, we use single-cell RNA-seq and spatial transcriptomics to investigate cellular interactions in pancreatic cancer. We identify close interactions between regulatory T cells (Tregs) and dendritic cells (DCs) and reveal potential cytokines that mediate these interactions. Experiments using differentiated DCs and Tregs show that Tregs induce the mature mregDC state, and that mregDCs, in turn, enhance Treg proliferation and activation. Together, these data suggest that DC–Treg proximity fuels a reinforcing feedback loop that may support the immunosuppressive TME in pancreatic cancer, and that blocking IL15 and Tnfsf11—the cytokines that mediate this signaling—may disrupt DC–Treg interactions while sparing CD8 T-cell activation in the TME.