Melatonin inhibits EMT and PD-L1 expression through the ERK1/2/FOSL1 pathway and regulates anti-tumor immunity in HNSCC.
Melatonin inhibits EMT and PD-L1 expression through the ERK1/2/FOSL1 pathway and regulates anti-tumor immunity in HNSCC.
复制标题
褪黑素通过ERK1/2/FOSL1途径抑制HNSCC中EMT和PD-L1的表达，调节HNSCC的抗肿瘤免疫。
作者：
褪黑激素是一种内源性激素，具有多种生物学功能，在多种恶性肿瘤中具有抗肿瘤特性。免疫逃逸是头颈部鳞状细胞癌（HNSCC）的重要标志之一，与肿瘤的进展密切相关。然而，褪黑素作为生理条件下的免疫调节剂，在HNSCC肿瘤免疫中的作用尚不清楚。在本研究中，我们发现HNSCC患者的内源性褪黑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，褪黑激素在体外和体内通过ERK 1/2/FOSL 1通路显著抑制HNSCC的程序性死亡配体1（PD-L1）表达并抑制上皮-间充质转化（EMT）。在SCC7/C3H同基因小鼠模型中，抗程序性死亡-1（PD-1）抗体与褪黑激素联合可显著抑制肿瘤生长，并通过增加肿瘤微环境中的CD8 + T细胞浸润和降低调节性T细胞（Treg）比例来调节抗肿瘤免疫。综上所述，褪黑激素通过ERK 1/2/FOSL 1通路抑制HNSCC中的EMT并下调PD-L1表达，并与抗PD-1抗体在体内发挥协同作用，这可能为HNSCC治疗提供有希望的策略。头颈部鳞状细胞癌（HNSCC）患者内源性褪黑素水平较低，且与淋巴结转移有关。此外，褪黑激素在体外和体内通过ERK 1/2/FOSL 1通路显著抑制HNSCC中的EMT并下调PD-L1表达。抗PD-1抗体与褪黑激素组合在SCC 7/C3H小鼠模型中显著抑制肿瘤生长并调节抗肿瘤免疫。
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. Endogenous melatonin levels were lower in head and neck squamous cell carcinoma (HNSCC) patients and related to lymph node metastasis. Moreover, melatonin significantly suppressed EMT and downregulated PD‐L1 expression in HNSCC through the ERK1/2/FOSL1 pathway in vitro and vivo. Anti‐PD‐1 antibody combined with melatonin significantly inhibited tumor growth and modulated anti‐tumor immunity in SCC7/C3H mouse models.
登录
查看更多内容
影响因子：
10.3
作者：
Cook, MR;Graham, C;Kheifets, L
通讯作者：
Kheifets, L
影响因子：
--
作者：
Ock CY;Kim S;Keam B;Kim M;Kim TM;Kim JH;Jeon YK;Lee JS;Kwon SK;Hah JH;Kwon TK;Kim DW;Wu HG;Sung MW;Heo DS
通讯作者：
Heo DS
影响因子：
8.8
作者：
Abiko, K.;Matsumura, N.;Hamanishi, J.;Horikawa, N.;Murakami, R.;Yamaguchi, K.;Yoshioka, Y.;Baba, T.;Konishi, I.;Mandai, M.
通讯作者：
Mandai, M.
PD-1检查点途径的分子和生化方面。
DOI：
10.1056/nejmra1514296
发表时间：
2016-11-03
期刊：
The New England journal of medicine
影响因子：
--
作者：
Boussiotis VA
通讯作者：
Boussiotis VA
影响因子：
5.6
作者：
Reiter RJ;Rosales-Corral SA;Tan DX;Acuna-Castroviejo D;Qin L;Yang SF;Xu K
通讯作者：
Xu K