VSIG4介导肿瘤相关巨噬细胞促未分化甲状腺癌免疫逃逸机制研究

Tumor-associated macrophages (TAMs) are key inflammatory cell populations that mediate tumor immune escape. Clinical samples have shown a large number of TAMs accumulating in anaplastic thyroid carcinoma (ATC) tissues, but the mechanisms and effects are unclear. Previous studies found that the TAM was strongly expressed in the immunosuppressive molecule VSIG4 and involved in T cell immune response. The vivo experiments show that VSIG4 can promote tumor growth by mediating immunosuppression, this effect may be related to VSIG4-binding T cell membrane receptor SPN inhibiting T cell killing function, suggesting that VSIG4-positive TAM may be a key subset of cells that promotes ATC immune escape. Based on this, the project will focus on the dialogue mechanism of ATC cell-TAM-T cells in immune escape. Including: 1) Clarifying the role of VSIG4-positive TAM in inhibiting killer T cells; 2) Illuminating the interaction of VSIG4-SPN mediating the ATC immune escape route; 3) Confirming the effect of VSIG4 expression on ATC tumor growth; 4) Interpreting the manner in which ATC cells promote TAM expression of VSIG4. It is expected that the pathway of VSIG4-mediated ATC immune escape will be elucidated and the new mechanism of tumor cells regulating the immune microenvironment will be revealed, providing a new target for ATC therapy.

肿瘤相关巨噬细胞（TAM）是介导肿瘤免疫逃逸的关键炎症细胞群，临床样本显示未分化甲状腺癌（ATC）组织中聚集大量TAM，然作用和机制未明。前期研究发现该TAM呈免疫抑制分子VSIG4强阳性表达，参与T细胞免疫应答；体内实验显示VSIG4可通过介导免疫抑制促肿瘤生长；该效应可能与VSIG4结合T细胞膜受体SPN抑制T细胞杀伤功能相关，提示VSIG4阳性TAM可能是促ATC免疫逃逸的关键细胞亚群。基于此，本项目将围绕ATC细胞-TAM-T细胞三者在免疫逃逸中的对话机制展开研究，包括：1）明确VSIG4阳性TAM抑制杀伤性T细胞的作用；2）阐明VSIG4-SPN相互作用介导ATC免疫逃逸途径；3）确证VSIG4表达对ATC肿瘤生长的效应；4）诠释ATC细胞促TAM表达VSIG4的方式。预期将阐明VSIG4介导ATC免疫逃逸的途径，揭示肿瘤细胞调控免疫微环境的全新机制，为ATC治疗提供新靶点。

未分化甲状腺癌（ATC）是一种极恶性的内分泌系统恶性肿瘤，临床治疗手段匮乏，尚无药物可阻止疾病快速进展。肿瘤相关巨噬细胞（TAM）是介导肿瘤免疫逃逸的关键炎症细胞群，临床样本显示ATC组织中聚集大量TAM，然而其作用和机制未明。本项目围绕ATC细胞-TAM-T细胞三者在免疫逃逸中的对话机制展开研究，旨在揭示肿瘤相关巨噬细胞（TAM）表达VSIG4介导ATC免疫逃逸的关键作用及机制。通过对ATC免疫检查点特征图谱筛选发现，VSIG4在ATC组织特异性上调，其上调倍数远高于经典免疫检查点（如CD274，TIGIT），并且与甲状腺癌患者预后负相关。单细胞转录组确证VSIG4在ATC组织巨噬细胞中高表达。进一步共培养实验显示，ATC细胞可诱导TAM表达VSIG4，进而抑制杀伤性T细胞的增殖、IL2及IFNγ分泌，敲降巨噬细胞VSIG4可逆转上述效应。通过杂交瘤实验制备、筛选了VSIG4特异性单克隆抗体8A6，体内外模型显示，靶向VSIG4单克隆抗体可显著恢复T细胞杀伤能力，明显抑制ATC肿瘤生长。进一步研究提示，VSIG4高表达与B细胞、CD8+ T 细胞，Tregs细胞的瘤内浸润高度相关。通过细胞因子芯片筛选结合共培养模型，确证ATC肿瘤细胞分泌CCL2诱导TAM高表达VSIG4。基于膜蛋白垂钓结合LC-MS/MS技术，团队鉴定了VSIG4通过结合T细胞膜受体SPN抑制T细胞的活化。进一步结果表明，VSIG4的Ig2片段是VSIG4结合SPN的关键区段。研究阐明VSIG4作为肿瘤细胞-TAM-T细胞之间“对话”的桥梁介导ATC免疫逃逸，揭示了肿瘤细胞调控免疫微环境的全新机制，为ATC免疫治疗提供新靶点。