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肿瘤树突状细胞中鞘脂激活蛋白原的高糖基化促使免疫逃逸
作者:小柯机器人 发布时间:2024/1/13 15:06:44

美国哈佛医学院Florian Winau小组发现,肿瘤树突状细胞中鞘脂激活蛋白原的高糖基化促使免疫逃逸。2024年1月12日,国际知名学术期刊《科学》发表了这一成果。

研究人员发现鞘脂激活蛋白原(pSAP)可驱动CD8 T细胞介导的肿瘤免疫,而其在肿瘤树突状细胞(DC)中的高糖基化可导致癌症免疫逃逸。研究人员发现溶酶体pSAP及其单saposin同源物介导了肿瘤细胞衍生的凋亡体的解体,从而促进膜相关抗原的呈现和T细胞的活化。在肿瘤微环境中,转化生长因子-β(TGF-β)诱导了pSAP的高糖基化及其随后的分泌,最终导致溶酶体溶酶体蛋白的耗竭。

在黑色素瘤患者的肿瘤相关直流细胞中也观察到了pSAP的高糖基化,用pSAP重组可挽救肿瘤浸润T细胞的活化。用重组pSAP靶向DC可触发肿瘤保护并增强免疫检查点疗法。这项研究证明了pSAP在肿瘤免疫中的关键功能,并可能支持其在免疫疗法中的作用。

据了解,肿瘤通过抑制抗原递呈来制定逃避免疫的策略。

附:英文原文

Title: Hyperglycosylation of prosaposin in tumor dendritic cells drives immune escape

Author: Pankaj Sharma, Xiaolong Zhang, Kevin Ly, Ji Hyung Kim, Qi Wan, Jessica Kim, Mumeng Lou, Lisa Kain, Luc Teyton, Florian Winau

Issue&Volume: 2024-01-12

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.

DOI: adg1955

Source: https://www.science.org/doi/10.1126/science.adg1955

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:63.714