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bioRxiv · 10.1101/2023.05.24.541931

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

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

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 the concept of TRAIL as a potent anticancer agent. Herein, we demonstrate that TRAIL+ cancer cells can leverage noncanonical TRAIL signaling in myeloid-derived suppressor cells (MDSCs) promoting their abundance 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 the abundance of MDSCs due to attenuation of MDSC proliferation. Noncanonical TRAIL signaling with consequent NF-{kappa}B activation in MDSCs facilitated enhanced MDSC proliferation. Single cell RNA sequencing and cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) of CD45+ cells in murine tumors from three distinct immunocompetent CCA models demonstrated a significant enrichment of an NF-{kappa}B activation signature in MDSCs. Moreover, MDSCs were resistant to TRAIL-mediated apoptosis due to enhanced expression of cellular FLICE inhibitory protein (cFLIP), an inhibitor of proapoptotic TRAIL signaling. Accordingly, cFLIP knockdown sensitized murine MDSCs to TRAIL-mediated apoptosis. Finally, cancer cell-restricted deletion of Trail significantly reduced MDSC abundance and murine tumor burden. In summary, our findings define a noncanonical TRAIL signal in MDSCs and highlight the therapeutic potential of targeting TRAIL+ cancer cells for the treatment of a poorly immunogenic cancer.

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Loeuillard, E., Li, B., Stumpf, H. E., Yang, J., Tomlinson, J. L., Graham, R. P., Smoot, R. L., Dong, H., Ilyas, S. I.. 2023-05-25. Noncanonical TRAIL Signaling Facilitates Tumor Immunosuppression and Cholangiocarcinoma Growth via Myeloid-Derived Suppressor Cells. https://doi.org/10.1101/2023.05.24.541931

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