Sharma, Zhang, and Ly et al. demonstrated a critical function of prosaposin (pSAP) in the processing and cross-presentation of membrane-associated antigens, but not of soluble antigens, for efficient CD8+ T cell activation and tumor control. Treatment of tumor DCs with recombinant pSAP activated melanoma-specific CD8+ T cells and boosted antitumor immunity. In the tumor microenvironment, TGFβ induced hyperglycosylation of pSAP in tumor DCs, leading to increased saposin secretion and immune evasion. Reconstitution with fully functional pSAP restored antigen presentation in tumor DCs, amplified T cell responses, and enhanced ICI therapy.
Contributed by Shishir Pant
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.