未分化甲状腺癌微环境区域免疫特征及其介导的免疫逃逸新机制

未分化甲状腺癌（ATC）是极恶性内分泌肿瘤，尚无有效治疗方案。免疫疗法在实体瘤治疗发展迅速，但ATC鲜有报道。项目组前期发现ATC大量浸润M2型肿瘤相关巨噬细胞（TAM），呈现典型的区域免疫学特征，多组学分析显示ATC具有内分泌肿瘤特征性表达分子，其机制可能与诱导TAM糖基化重编程有关。进一步研究显示候选免疫抑制分子VSIG4参与免疫逃逸，且其单抗具显著抗肿瘤活性。提示诠释ATC调控TAM免疫特征及机制有望发展创新免疫治疗。据此，项目展开如下研究：利用二代测序等明确ATC免疫图谱及TAM免疫特征；采用体内外模型确证TAM介导免疫逃逸作用，并验证单抗抗肿瘤活性；基于糖基化蛋白组学、点突变等技术明确TAM糖基化重编程介导免疫逃逸作用及机制；利用细胞因子芯片、代谢组学手段阐明ATC与TAM对话机制。预期将明确ATC区域免疫特征，揭示肿瘤细胞塑造免疫抑制微环境的全新机制，为ATC免疫治疗提供依据。

Anaplastic thyroid carcinoma (ATC) is an extremely malignant endocrine carcinoma, and there is no effective treatment. Immunotherapy is developing rapidly in solid tumor treatment, while it is rarely reported in ATC. The project team found that ATC was abundantly infiltrated with M2 type tumor-associated macrophages (TAMs), presenting typical regional immunity features. Multi-omics analysis showed that ATC expressed endocrine tumor-specific molecules, and the mechanism may be related to the manipulation of TAM glycosylation reprogramming. Further studies showed that the candidate immunosuppressive molecule VSIG4 was involved in immune escape, and its monoclonal antibody had significant antitumor activity. These results suggest that demonstrate the immune characteristics and mechanisms of TAM regulated by ATC hold promise to develop novel immunotherapy. Accordingly, our project will carry out the following research: Defining the ATC immune profiling and TAM immune characteristics by using the next generation sequencing; confirming the immune escape effect of TAM and verifying the anti-tumor activity of monoclonal antibodies by using in vivo and in vitro models; demonstrating the immune escape effect and mechanism mediated by TAM glycosylation reprogramming based on glycosylation proteomics, base substitution and other technologies; elucidating the crosstalk mechanism between ATC and TAM by using cytokine chip, metabolomics. All these researches aim at clarifying the characteristics of ATC regional immunity, and revealing a brand-new mechanism of immunosuppressive microenvironment shaped by tumor cells, which will provide a rational basis for ATC immunotherapy.