Noncanonical TRAIL Signaling Facilitates Tumor Immunosuppression and Cholangiocarcinoma Growth via Myeloid-Derived Suppressor Cells.

Proapoptotic tumor necrosis factor related apoptosis inducing ligand (TRAIL) signaling as a cause of cancer cell death is a well-established mechanism. However, TRAIL-receptor (TRAIL-R) agonists have had very limited anticancer activity in humans, challenging this concept of TRAIL as a potent anticancer agent. Herein, we demonstrate that TRAIL+ cancer cells can leverage non-canonical TRAIL signaling to foster myeloid-derived suppressor cell (MDSC) accumulation in murine cholangiocarcinoma (CCA). In multiple immunocompetent syngeneic, orthotopic murine models of CCA, implantation of TRAIL+ murine cancer cells into Trail-r -/- mice resulted in a significant reduction in tumor volumes compared to wild-type mice. Tumor bearing Trail-r -/- mice had a significant decrease in abundance of MDSCs. Accordingly, genetic deletion of Trail-r decreased murine tumor progression via a significant reduction in MDSCs due to attenuation of MDSC proliferation. Moreover, MDSCs were resistant to TRAIL-mediated apoptosis, and noncanonical TRAIL signaling activated NF-κB signaling in MDSCs. Finally, cancer cell restricted deletion of Trail significantly reduces tumor burden. In summary, our findings highlight the therapeutic potential of targeting TRAIL+ cancer cells for the treatment of a poorly immunogenic cancer.