Alterations of ceramide synthesis induce PD-L1 internalization and signaling to regulate tumor metastasis and immunotherapy response

Wofford W., Kim J., Kim D., Janneh A. H., Lee H. G., Atilgan F. C., ...More

Cell Reports, vol.43, no.8, 2024 (SCI-Expanded) identifier identifier

  • Publication Type: Article / Article
  • Volume: 43 Issue: 8
  • Publication Date: 2024
  • Doi Number: 10.1016/j.celrep.2024.114532
  • Journal Name: Cell Reports
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, BIOSIS, Chemical Abstracts Core, EMBASE, MEDLINE, Directory of Open Access Journals
  • Keywords: ceramide, CerS4, CP: Cancer, CP: Metabolism, immunotherapy, metastasis, PD-L1, sonic hedgehog, sphingolipid
  • Istanbul Medipol University Affiliated: Yes

Abstract

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 β 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 β-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.