Regulation of programmed-death ligand in the human head and neck squamous cell carcinoma microenvironment is mediated through matrix metalloproteinase-mediated proteolytic cleavage.
Regulation of programmed-death ligand in the human head and neck squamous cell carcinoma microenvironment is mediated through matrix metalloproteinase-mediated proteolytic cleavage.
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DOI：
10.3892/ijo.2017.4221
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发表时间：
2018-03
影响因子：
5.2
通讯作者：
Kawashiri S
中科院分区：
文献类型：
--
作者：
Hira-Miyazawa M;Nakamura H;Hirai M;Kobayashi Y;Kitahara H;Bou-Gharios G;Kawashiri S
复发性和/或转移性头颈部鳞状细胞癌（R/M HNSCC）是一种预后不良的破坏性恶性肿瘤。最近的临床研究表明，阻断程序性死亡受体-1 (PD-1)/程序性死亡配体1 （PD-L1）通路可有效降低肿瘤生长，提高生存率。由于HNSCC具有高度的免疫抑制作用，PD-L1表达被认为是一种潜在的致病机制。然而，抗pd -1治疗仅对某些患者有益。因此，控制PD-L1表达的机制需要进一步研究，以便更好地了解单独或联合抗pd -1治疗的疗效预测和优化。本研究发现，尽管在OSC-20细胞总裂解液中PD-L1的表达高于OSC-19细胞，但与OSC-19细胞相比，从细胞膜中提取的PD-L1蛋白在OSC-20细胞中表达下调。发现几种基质金属蛋白酶（MMPs）在HNSCC中上调；其中，MMP-7和-13在OSC-20细胞中的表达明显高于OSC-19细胞。用重组MMP-13和-7降解纯化的PD-L1。MMP-13特异性抑制剂CL82198显著恢复了PD-L1的表达，提示MMP-13参与了OSC-20细胞中PD-L1的脱落/裂解。在常规用于治疗HNSCC患者的抗癌药物中，紫杉醇增加了无/与树突状细胞（DCs）共培养的R/M HNSCC细胞（HOC313细胞）中MMP-13的表达。这些结果表明，MMP-13对PD-L1的脱落/切割是其抗侵袭和转移保护作用的机制之一。因此，MMP-13作为预测抗pd -1治疗疗效下降的标志物具有潜在价值。此外，紫杉醇与抗pd -1治疗联合治疗R/M型HNSCC是一个特别有希望的候选者。
Recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. According to recent clinical studies, tumour growth can be effectively reduced and survival can be improved by blocking the programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway. PD-L1 expression has been proposed as a potential causative mechanism, as HNSCC is highly immunosuppressive. However, anti-PD-1 treatment is beneficial only for certain patients. Therefore, the mechanisms controlling PD-L1 expression warrant further investigation in order to provide a better understanding of the predicting efficacy of and optimising anti-PD-1 therapy, alone or in combination. In this study, PD-L1 protein extracted from the cell membrane was found to be downregulated in OSC-20 cells compared with OSC-19 cells, despite a higher PD-L1 expression in the total cell lysate of the OSC-20 compared with the OSC-19 cells. Several matrix metalloproteinases (MMPs) were found to be upregulated in HNSCC; in particular, MMP-7 and -13 were upregulated in the OSC-20 compared with the OSC-19 cells. Purified PD-L1 was degraded by recombinant MMP-13 and -7. The expression of PD-L1 was significantly restored by a specific inhibitor of MMP-13 (CL82198), which suggested the involvement of MMP-13 in the shedding/cleavage of PD-L1 in the OSC-20 cells. Among the anticancer drugs conventionally used in the treatment of patients with HNSCC, paclitaxel increased MMP-13 expression in R/M HNSCC cells (HOC313 cells) co-cultured without/with dendritic cells (DCs). These results suggest that the shedding/cleavage of PD-L1 by MMP-13 is one of the mechanisms behind the protective effect against invasion and metastasis. Thus, MMP-13 has potential value as a marker predictive of the decreased efficacy of anti-PD-1 therapy. In addition, paclitaxel is a particularly promising candidate for combination therapy in R/M HNSCC with anti-PD-1 therapy.
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影响因子：
8.8
作者：
Fukuda, H.;Mochizuki, S.;Abe, H.;Okano, H. J.;Hara-Miyauchi, C.;Okano, H.;Yamaguchi, N.;Nakayama, M.;D'Armiento, J.;Okada, Y.
通讯作者：
Okada, Y.
影响因子：
5.2
作者：
Hirai M;Kitahara H;Kobayashi Y;Kato K;Bou-Gharios G;Nakamura H;Kawashiri S
通讯作者：
Kawashiri S
影响因子：
4.2
作者：
Kitahara H;Hirai M;Kato K;Bou-Gharios G;Nakamura H;Kawashiri S
通讯作者：
Kawashiri S
影响因子：
11.5
作者：
Konishi, J;Yamazaki, K;Nishimura, M
通讯作者：
Nishimura, M
影响因子：
11.2
作者：
Acuff, Heath B.;Sinnamon, Mark;Matrisian, Lynn M.
通讯作者：
Matrisian, Lynn M.