肿瘤微环境中钙联蛋白Calnexin独立或协同Calreticulin介导口腔鳞癌免疫编辑的机制

How to detect malignant transformation of oral leukoplakia in early stage and predict prognosis and finally find effective targeted drugs are urgently needed to be solved in clinical. Pivotal molecules in the developing of oral cancer is the key to uncover the mechanism of canceration and develop the targeted medicine. Calnexin is type I transmembrane protein in endoplasmic reticulum, a class lectin molecular chaperone, containing highly conservative rat domain structure. Our previous proteomic study showed that the total proteins and its phosphorylation are highly expressed in tumor. preliminary experiments displayed that it can combine with T lymphocytes and inhibit its proliferation, which prompted that calnexin is responsible for influencing biological types of cancer epithelial intracellularlly, and affect the function of T lymphocytes and macrophages through intracellular to cell membrane, although the mechanism is unclear. Therein, we hypothesized that calnexin interact with calreticulin as molecular chaperone to promote the function of "eat me signal", and influencing the tumor behavior through balancing tumor escape of CD47. It can also act on T lymphocytes to induce tumor killing or escaping. We will observe biological behavior of tumor epithelial by analyzing its expression and prognosis and silencing its gene. Furthermore, we will conduct experiments in human and rat in vivo and vitro to regulate tumor killing and escaping through macrophages. We will utilize the receptor array system to screen and identify calnexin T cell surface receptors.And fully disclose the core value of calnexin in tumor immune editing mechanism in oral tumor environment.

如何早期检测白斑癌变，判定癌变预后并寻找治疗靶标是临床亟待解决的难题，发现癌变关键分子是核心。内质网I型跨膜蛋白Calnexin是重要的类凝集素分子伴侣，含人鼠高度保守结构域。预实验显示其与口腔鳞癌不良预后相关，可与巨噬细胞和T淋巴细胞结合，并可抑制T淋巴细胞增殖，显示其可能具肿瘤免疫编辑新功能。由此设想：作为伴侣分子，Calnexin可与Calreticulin协同促进肿瘤"eat me signal"功能，且与CD47肿瘤逃逸相互平衡而影响肿瘤行为。也可独立作用于T淋巴细胞诱导肿瘤逃逸。我们将通过分析Calnexin临床表达与预后，沉默该基因观察口腔鳞癌细胞体内外生物学表型，及行人、鼠Calnexin通过巨噬细胞或T淋巴细胞调控肿瘤免疫杀伤或逃逸的体内外研究，并拟用受体芯片系统筛选鉴定CalnexinT细胞表面受体，从而全面揭示Calnexin为核心的肿瘤免疫编辑调控肿瘤发生转移的机理

如何早期检测白斑癌变，判定癌变预后并寻找治疗靶标是临床亟待解决的难题，发现癌变关键分子是核心。内质网I型跨膜蛋白Calnexin是重要的类凝集素分子伴侣，含人鼠高度保守结构域。预实验显示其与口腔鳞癌不良预后相关，可与巨噬细胞和T淋巴细胞结合，并可抑制T淋巴细胞增殖，显示其可能具肿瘤免疫编辑新功能。Calnexin在口腔鳞癌肿瘤微环境中调控肿瘤上皮细胞与免疫细胞的交互作用，从而影响肿瘤发生与转移的机理。本项目重点研究Calnexin在临床样本中的表达特征与预后的关系；Calnexin在口腔鳞癌中的生物学行为的体内、外研究及Calnexin影响T淋巴细胞的体外增殖杀伤和体内效应功能。研究发现：1）Calnexin在OSCC细胞和肿瘤组织中高表达，其膜蛋白表达是影响总生存时间（OS）的重要因素；2）Calnexin抑制人T淋巴细胞增殖和效能，抑制T细胞抗肿瘤反应，调控肿瘤生长；3）揭示了Calnexin可能通过PD1负调控T细胞免疫功能的表型及机制，Calnexin有望成为独立或者联合PD1行肿瘤免疫治疗的新靶点；4）PD1/PDL1抗体治疗可以有效阻断口腔黏膜上皮的恶性转化；5）进一步明确口腔黏膜癌变中免疫微环境特征显示异位淋巴结构TLS 、肿瘤抗原交叉呈递细胞CD141+DCs、间充质干细胞、foxp3上皮异位表达等特异性参与口腔上皮恶性转化。本项目申请了该分子在筛选用于诊断或治疗肿瘤相关疾病的药物中的用途的发明专利（专利号201710002155.2），获得相关的应用成果；发表标注SCI 收录论文 8 篇，总 IF 值 40.78 分，包括中科院JCR一区杂志2篇，JCR二区杂志4篇，其中Calnexin抑制T细胞抗肿瘤功能的主体研究发表于 Cancer Immunology Research（IF ：9.188）；期间获中华口腔医学会科技奖一等奖（排名第四）。期间培养毕业硕士生 3 名，博士生4 名。