PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPα axis in HPV negative head and neck squamous cell carcinoma.
PD-1 blockade attenuates immunosuppressive myeloid cells due to inhibition of CD47/SIRPα axis in HPV negative head and neck squamous cell carcinoma.
复制标题
在 HPV 阴性头颈鳞状细胞癌中，PD-1 阻断可通过抑制 CD47/SIRPα 轴来减弱免疫抑制性骨髓细胞。
DOI：
10.18632/oncotarget.5955
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发表时间：
2015-12-08
期刊：
影响因子：
--
通讯作者：
Sun ZJ
中科院分区：
文献类型：
--
作者：
Yu GT;Bu LL;Huang CF;Zhang WF;Chen WJ;Gutkind JS;Kulkarni AB;Sun ZJ
骨髓源性抑制细胞（MDSC）和肿瘤相关巨噬细胞（TAM）在肿瘤免疫抑制网络和肿瘤进展中起着关键作用。然而，程序性死亡-1（PD-1）在头颈部鳞状细胞癌（HNSCC）中MDSC和TAM的免疫功能中的确切作用尚未明确阐明。在本研究中，我们发现PD-1和PD-L1水平在人HNSCC标本中显著高于正常口腔粘膜。MDSC和TAM在小鼠和人HNSCC标本中表征，与PD-1和PD-L1表达良好相关。αPD-1给药耐受性良好，沿着免疫器官和肿瘤中MDSC和TAM的显著减少，显著降低了HNSCC小鼠模型中的肿瘤生长。分子分析表明，PD-1阻断可降低CD 47/SIRPα通路，从而调节MDSC、TAM、树突状细胞以及效应T细胞。因此，这些数据确定PD-1/PD-L1轴在人和小鼠HNSCC中显著增加。αPD-1免疫治疗可能为调节HNSCC的微环境和宏观环境提供一种新的治疗方法。
Myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs) play key roles in the tumor immune suppressive network and tumor progression. However, precise roles of programmed death-1 (PD-1) in immunological functions of MDSCs and TAMs in head and neck squamous cell carcinoma (HNSCC) have not been clearly elucidated. In the present study, we show that PD-1 and PD-L1 levels were significantly higher in human HNSCC specimen than in normal oral mucosa. MDSCs and TAMs were characterized in mice and human HNSCC specimen, correlated well with PD-1 and PD-L1 expression. αPD-1 treatment was well tolerated and significantly reduced tumor growth in the HNSCC mouse model along with significant reduction in MDSCs and TAMs in immune organs and tumors. Molecular analysis suggests a reduction in the CD47/SIRPα pathway by PD-1 blockade, which regulates MDSCs, TAMs, dendritic cell as well as effector T cells. Hence, these data identify that PD-1/PD-L1 axis is significantly increased in human and mouse HNSCC. Adoptive αPD-1 immunotherapy may provide a novel therapeutic approach to modulate the micro- and macro- environment in HNSCC.