褪黑激素通过 ERK1/2/FOSL1 通路抑制 EMT 和 PD-L1 表达并调节 HNSCC 的抗肿瘤免疫,Cancer Science

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褪黑激素通过 ERK1/2/FOSL1 通路抑制 EMT 和 PD-L1 表达并调节 HNSCC 的抗肿瘤免疫
Cancer Science ( IF 4.5 ) Pub Date : 2022-03-17 , DOI: 10.1111/cas.15338
Xinyue Luo ₁ , Yang Chen ₁ , Hokeung Tang ₁ , Hui Wang ₁ , Erhui Jiang _{1,

2} , Zhe Shao _{1,

2} , Ke Liu _{1,

2} , Xiaocheng Zhou _{1,

3} , Zhengjun Shang _{1,

2}

Affiliation

褪黑激素是一种具有多种生物学功能的内源性激素，在多种恶性肿瘤中具有抗肿瘤作用。免疫逃避是头颈部鳞状细胞癌（HNSCC）最重要的标志之一，与肿瘤进展密切相关。然而，作为生理条件下的免疫调节剂，褪黑激素在 HNSCC 肿瘤免疫中的作用仍不清楚。在本研究中，我们发现 HNSCC 患者的内源性褪黑激素水平低于头颈部良性肿瘤患者。重要的是，较低的褪黑激素水平与 HNSCC 患者的淋巴结转移有关。此外，褪黑激素通过 ERK1/2/FOSL1 通路显着抑制程序性死亡配体 1 (PD-L1) 的表达并抑制 HNSCC 的上皮间质转化 (EMT)体外和体内。在 SCC7/C3H 同基因小鼠模型中，抗程序性死亡 1 (PD-1) 抗体联合褪黑激素通过增加 CD8 ⁺ T 细胞浸润和降低调节性 T 细胞 (Treg) 比例显着抑制肿瘤生长并调节抗肿瘤免疫在肿瘤微环境中。总之，褪黑激素通过ERK1/2/FOSL1通路抑制HNSCC的EMT并下调PD-L1的表达，并在体内与抗PD-1抗体发挥协同作用，可为HNSCC的治疗提供有希望的策略。

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Melatonin inhibits EMT and PD-L1 expression through the ERK1/2/FOSL1 pathway and regulates anti-tumor immunity in HNSCC

Melatonin is an endogenous hormone with various biological functions and possesses anti-tumor properties in multiple malignancies. Immune evasion is one of the most important hallmarks of head and neck squamous cell carcinoma (HNSCC) and is closely related to tumor progression. However, as an immune modulator under physiological conditions, the roles of melatonin in tumor immunity in HNSCC remains unclear. In this study, we found that the endogenous melatonin levels in patients with HNSCC were lower than those in patients with benign tumors in head and neck. Importantly, lower melatonin levels were related to lymph node metastasis among patients with HNSCC. Moreover, melatonin significantly suppressed programmed death-ligand 1 (PD-L1) expression and inhibited epithelial–mesenchymal transition (EMT) of HNSCC through the ERK1/2/FOSL1 pathway in vitro and in vivo. In SCC7/C3H syngeneic mouse models, anti-programmed death-1 (PD-1) antibody combined with melatonin significantly inhibited tumor growth and modulated anti-tumor immunity by increasing CD8⁺ T cell infiltration and decreasing the regulatory T cell (Treg) proportion in the tumor microenvironment. Taken together, melatonin inhibited EMT and downregulated PD-L1 expression in HNSCC through the ERK1/2/FOSL1 pathway and exerted synergistic effects with anti-PD-1 antibody in vivo, which could provide promising strategies for HNSCC treatment.

更新日期：2022-03-17

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