GM-CSF通过STAT5/PPAR-γ/FATPs介导PD-L1highCXCR4highCD62Llow肿瘤相关中性粒细胞脂质代谢重编程促进喉癌免疫抑制的机制研究

局晚期喉癌患者生存率低、生活质量差，抑制性微环境是限制免疫治疗的重要瓶颈。前期我们首次证实，喉癌局部GM-CSF重塑肿瘤相关中性粒细胞TAN表型功能，凋亡减少、寿命延长、PD-L1增加、抑制T细胞增殖活化，促进免疫逃逸，与不良预后相关。预实验发现TAN呈CXCR4highCD62Llow衰老表型，脂含量、脂肪酸氧化增加，脂肪酸转运蛋白FATPs、脂代谢转录因子PPAR-γ上调，预示发生脂代谢重编程，脂代谢被认为与免疫抑制相关。结合文献、预测软件，FATPs启动子存在与GM-CSF下游STAT5及PPAR-γ结合位点，提出假说：GM-CSF通过STAT5/PPAR-γ/FATPs介导TAN脂代谢重编程，促进免疫抑制。本研究拟阐明TAN代谢模式及调控机制，探索干预GM-CSF下游STAT5/PPAR-γ/FATPs重塑TAN脂代谢、逆转免疫抑制的可能，这将为喉癌免疫治疗联合代谢干预提供新思路。

The survival rate and the life quality of locally advanced laryngeal squamous cell carcinoma (LSCC) patients has not significantly improved. Immunosuppressive tumor microenvironment acts as the important bottleneck that limits effective response to cancer immunotherapy. Our previous work confirmed for the first time that tumor-derived GM-CSF reprogrammed the phenotype and function of tumor-associated neutrophils (TANs), displaying the key immunosuppression features of less apoptosis, prolonged lifespan, more PD-L1 expression, more inhibition of T cell proliferation and activation, which was associated with poor outcome in human LSCC. Our preliminary study further demonstrated that TANs displayed CXCR4highCD62Llow aged phenotype with increased lipids and fatty acid oxidation and up-regulated fatty acid transport proteins (FATPs) and lipid metabolism-associated transcription factor PPAR-γ, indicating TANs undergoing lipid metabolism reprogramming related with immune suppression. According to previous study and predictive software, there are binding sites with GM-CSF downstream STAT5 and PPAR-γ in the promoter region of FATPs. Herein, we hypothesized that tumor-derived GM-CSF induced lipid metabolism reprogramming of TANs through STAT5/PPAR-γ/FATPs, which contributed to the immunosuppressive environment in LSCC. This study will thoroughly elucidate the metabolic pattern and regulatory mechanism of TANs, further explore the possibility of reversing tumor evasion by targeting STAT5/PPAR-γ/FATPs on TANs, which will provide new direction for LSCC immunotherapy combination with metabolic intervention.