DOI: 10.1101/2023.05.24.541931

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

E.Loeuillard B. Li H. E. Stumpf J. Yang J. L. Tomlinson R. P. Graham R. L. Smoot H. Dong S. I. Ilyas

E.Loeuillard B. Li H. E. Stumpf ...+5 S. I. Ilyas

摘要

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-{kappa}B 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.

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