| First Author | Wofford W | Year | 2024 |
| Journal | Cell Rep | Volume | 43 |
| Issue | 8 | Pages | 114532 |
| PubMed ID | 39046874 | Mgi Jnum | J:353583 |
| Mgi Id | MGI:7716366 | Doi | 10.1016/j.celrep.2024.114532 |
| Citation | Wofford W, et al. (2024) Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response. Cell Rep 43(8):114532 |
| abstractText | Programmed death ligand 1, PD-L1 (CD274), facilitates immune evasion and exerts pro-survival functions in cancer cells. Here, we report a mechanism whereby internalization of PD-L1 in response to alterations of bioactive lipid/ceramide metabolism by ceramide synthase 4 (CerS4) induces sonic hedgehog (Shh) and transforming growth factor beta receptor signaling to enhance tumor metastasis in triple-negative breast cancers (TNBCs), exhibiting immunotherapy resistance. Mechanistically, data showed that internalized PD-L1 interacts with an RNA-binding protein, caprin-1, to stabilize Shh/TGFBR1/Wnt mRNAs to induce beta-catenin signaling and TNBC growth/metastasis, consistent with increased infiltration of FoxP3(+) regulatory T cells and resistance to immunotherapy. While mammary tumors developed in MMTV-PyMT/CerS4(-/-) were highly metastatic, targeting the Shh/PD-L1 axis using sonidegib and anti-PD-L1 antibody vastly decreased tumor growth and metastasis, consistent with the inhibition of PD-L1 internalization and Shh/Wnt signaling, restoring anti-tumor immune response. These data, validated in clinical samples and databases, provide a mechanism-based therapeutic strategy to improve immunotherapy responses in metastatic TNBCs. |
