Hyperglycosylation of prosaposin in tumor DCs promotes immune escape in cancer.

Tumors develop strategies to evade immunity by suppressing antigen presentation. Here, we show that prosaposin drives CD8 T cell-mediated tumor immunity and that its hyperglycosylation in tumor DCs leads to cancer immune escape. We found that lysosomal prosaposin 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, TGF-β induced hyperglycosylation of prosaposin and its subsequent secretion, which ultimately caused depletion of lysosomal saposins. In melanoma patients, we found similar prosaposin hyperglycosylation in tumor-associated DCs, and reconstitution with prosaposin rescued activation of tumor-infiltrating T cells. Targeting tumor DCs with recombinant prosaposin triggered cancer protection and enhanced immune checkpoint therapy. Our studies demonstrate a critical function of prosaposin in tumor immunity and escape and introduce a novel principle of prosaposin-based cancer immunotherapy. Prosaposin facilitates antigen cross-presentation and tumor immunity and its hyperglycosylation leads to immune evasion.

Citation

Pankaj Sharma, Xiaolong Zhang, Kevin Ly, Ji Hyung Kim, Qi Wan, Jessica Kim, Mumeng Lou, Lisa Kain, Luc Teyton, Florian Winau. Hyperglycosylation of prosaposin in tumor DCs promotes immune escape in cancer. bioRxiv : the preprint server for biology. 2023 Jun 14

PMID: 37398287

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