Hyperglycosylation of prosaposin in tumor dendritic cells drives immune escape

Science. 2024 Jan 12;383(6679):190-200. doi: 10.1126/science.adg1955. Epub 2024 Jan 11.

Abstract

Tumors develop strategies to evade immunity by suppressing antigen presentation. In this work, we show that prosaposin (pSAP) drives CD8 T cell-mediated tumor immunity and that its hyperglycosylation in tumor dendritic cells (DCs) leads to cancer immune escape. We found that lysosomal pSAP and its single-saposin cognates mediated disintegration of tumor cell-derived apoptotic bodies to facilitate presentation of membrane-associated antigen and T cell activation. In the tumor microenvironment, transforming growth factor-β (TGF-β) induced hyperglycosylation of pSAP and its subsequent secretion, which ultimately caused depletion of lysosomal saposins. pSAP hyperglycosylation was also observed in tumor-associated DCs from melanoma patients, and reconstitution with pSAP rescued activation of tumor-infiltrating T cells. Targeting DCs with recombinant pSAP triggered tumor protection and enhanced immune checkpoint therapy. Our studies demonstrate a critical function of pSAP in tumor immunity and may support its role in immunotherapy.

MeSH terms

  • Antigen Presentation
  • CD8-Positive T-Lymphocytes* / immunology
  • Dendritic Cells / immunology
  • Glycosylation
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunotherapy
  • Neoplasms* / immunology
  • Neoplasms* / pathology
  • Neoplasms* / therapy
  • Saposins* / metabolism
  • Transforming Growth Factor beta / metabolism
  • Tumor Escape*
  • Tumor Microenvironment

Substances

  • Saposins
  • Transforming Growth Factor beta
  • PSAP protein, human
  • Immune Checkpoint Inhibitors