微环境肿瘤相关巨噬细胞（TAMs）在肿瘤恶性进展中的作用备受关注。我们发现MTDH+ TAMs细胞可高表达CCL18，促进头颈鳞癌的血管新生和侵袭转移；MTDH+ TAMs细胞可能存在miR-18a-5p/HIF-1α/CCL18信号轴。据此推测MTDH+ TAMs细胞可能经miR-18a-5p/HIF-1α上调CCL18，结合肿瘤细胞和血管内皮细胞表面受体Nir1，增强头颈鳞癌细胞的侵袭转移，并招募血管内皮细胞促进血管新生，共同导致侵袭转移。为此，我们将经体内外实验进一步阐明miR-18a-5p/HIF-1α/CCL18信号轴是否参与MTDH+ TAM细胞介导的血管新生和转移，重点阐明该信号轴的内在调控机制并验证其临床价值。本项目将证实该信号轴可作为“分子桥梁”衔接肿瘤细胞、血管内皮细胞和TAMs细胞共同导致转移；加深对头颈鳞癌免疫炎性微环境的认识，为靶向TAMs的免疫治疗提供实验数据。

Tumor-associated macrophages (TAMs) in tumor microenvironment function importantly and is intensively investigated in cancer malignant progression. Our previous results indicate that MTDH+ tumor associated macrophages (TAMs) overexpress cytokine CCL18, which enhances angiogenesis and metastasis in of squamous cell carcinoma of the head and neck (SCCHN). Moreover, a potential miR-18a-5p/HIF-1α/CCL18 signaling axis may exist in MTDH+ TAMs. Therefore, we hypothesize that MTDH+ TAMs may regulate the expression of CCL18 that binds to its receptor Nir1 on cell surfaces of SCCHN and vascular endothelial cells via miR-18a-5p/HIF-1α/CCL18 signaling axis. Moreover, CCL18/Nir1 bindings may enhance metastatic ability of SCCHN cells themselves and recruit vascular endothelial cells to form angiogenesis, which together promotes SCCHN metastasis. To confirm this hypothesis, both in vitro and in vivo experiments will be used to observe whether miR-18a-5p/HIF-1α/CCL18 signaling axis will participate in MTDH+ TAMs mediated angiogenesis and metastasis in SCCHN. In this program, we will focus on the molecular regulation mechanisms of the above signaling pathway in TAMs. Finally, the clinical significance of this signaling axis will be investigated in a large SCCHN specimens with intact clinical information. The success of this project will help us to confirm that MTDH/miR-18a-5p/HIF-1α/CCL18 signaling axis can serve as a molecular bridge to connect tumor cells, vascular endothelial cells and TAMs, which will deepen our understanding about immunological and inflammatory microenvironment in SCCHN and further benefit our future immunotherapy targeting TAMs.