免疫系统
癌症免疫疗法
交叉展示
肿瘤微环境
免疫疗法
抗原呈递
免疫
肿瘤抗原
分泌物
抗原
免疫逃逸
癌症
生物
癌症研究
免疫学
T细胞
生物化学
遗传学
作者
Pankaj Sharma,Xiaolong Zhang,Kévin Ly,Ji Hyung Kim,Qi Wan,Jessica Kim,Min Lou,Lisa Kain,Luc Teyton,Florian Winau
标识
DOI:10.1101/2023.06.14.545005
摘要
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.
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