RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题:The validity of immunotherapy against palate mucoepidermoid carcinoma based on data enrichment from oral cancer database.
The validity of immunotherapy against palate mucoepidermoid carcinoma based on data enrichment from oral cancer database.
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本研究提出了一种新思路:针对 PMEC 这类少见癌种的免疫治疗靶点,仍可借助其上级分类的数据扩充来确定。
腭部黏液表皮样癌(PMEC)是一种少见但治疗困难的口腔癌亚型。由于缺乏针对PMEC的独立、全面数据库,筛选PMEC靶向蛋白可能不够准确。不过,目前已建立并上传了多个基于口腔癌的基因表达数据库。结合数据富集分析和实验验证,有望确定PMEC的合适靶蛋白。
我们首先检索多个口腔癌相关数据库,比较肿瘤组织与正常组织的基因表达特征,并从重叠的差异基因中筛选候选靶点。同时建立不同体外和离体模型验证靶蛋白,以确定其用于免疫治疗的有效性。
4个数据库的交集区域包含744个基因,进一步富集分析筛出12个基因用于蛋白表达谱评估。随后选择CD276和CD6两种靶蛋白,并构建相应CAR-NK细胞。根据其对细胞系、原代肿瘤细胞和类器官的杀伤效率分析,最终确认CD276为靶蛋白。
本研究提出一种新思路:即使对于PMEC这类少见癌症,也可借助其上位类别的数据富集来确定免疫治疗靶点。更重要的是,将数据库分析与多种实验室模型验证相结合,有助于更准确地筛选靶蛋白。
Palate mucoepidermoid carcinoma (PMEC) is an infrequent but tough subtype of oral carcinoma. Due to the lack of independent and comprehensive database for PMEC, the selection or screening of targeted protein on PMEC might be inaccurate. However, several databases of gene expression based on oral cancers having been constructed and uploaded. With the help of combining data enrichment and lab experiments, the target protein choosing against PMEC could be available. METHOD: We firstly searched multiple databases, which being relevant with oral cancers, and compared the gene expression property between tumor tissues and normal tissues. From the overlapped differential genes, we chose several candidates. Meanwhile, we cultured different in vitro and ex vivo models for the targeted protein verification, to ascertain its effectiveness to the immunotherapy. RESULT: 744 genes were in the overlapped region from the 4 different databases. Among those genes, we further enriched 12 for the protein expression profiling. Then two target proteins, CD276 and CD6, were selected and constructed on the CAR-NK cells. Based on the killing efficiency analysis with cell line, tumor primary cells and organoids. The final targeted protein CD276 had been confirmed.
This research provided a new mentality that the target of immunotherapy on such infrequent carcinoma, PMEC, could still be determined with the data enrichment from its upper category. More importantly, the combination of database analysis with multi-model's verification in lab helped the targeted protein selection more precisely.
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