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.

ONE SENTENCE SUMMARY: Prosaposin facilitates antigen cross-presentation and tumor immunity and its hyperglycosylation leads to immune evasion.