Hyperglycosylation of prosaposin in tumor dendritic cells drives immune escape

• 成果类型: Article
• 署名作者: Sharma, Pankaj; Zhang, Xiaolong; Ly, Kevin; Kim, Ji Hyung; Wan, Qi; Kim, Jessica; Lou, Mumeng; Kain, Lisa; Teyton, Luc; Winau, Florian
• 署名单位: Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; Program in Cellular & Molecular Medicine (PCMM); Harvard Medical School; Scripps Research Institute
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13268
• DOI: 10.1126/science.adg1955
• 发表日期: 2024-01-12
• 页码: 190-200
• 关键词: sphingolipid activator proteins; t-cells; stimulation; TRAFFICKING; antigens; binding; innate; pd-l1

摘要

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-beta (TGF-beta) 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.