Open Access

Regulation of programmed-death ligand in the human head and neck squamous cell carcinoma microenvironment is mediated through matrix metalloproteinase-mediated proteolytic cleavage

  • Authors:
    • Mayuko Hira-Miyazawa
    • Hiroyuki Nakamura
    • Mariko Hirai
    • Yutaka Kobayashi
    • Hiroko Kitahara
    • George Bou-Gharios
    • Shuichi Kawashiri
  • View Affiliations

  • Published online on: December 11, 2017     https://doi.org/10.3892/ijo.2017.4221
  • Pages:379-388
  • Copyright: © Hira-Miyazawa et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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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February 2018
Volume 52 Issue 2

Print ISSN: 1019-6439
Online ISSN:1791-2423

2016 Impact Factor: 3.079
Ranked #33/217 Oncology
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APA
Hira-Miyazawa, M., Nakamura, H., Hirai, M., Kobayashi, Y., Kitahara, H., Bou-Gharios, G., & Kawashiri, S. (2018). Regulation of programmed-death ligand in the human head and neck squamous cell carcinoma microenvironment is mediated through matrix metalloproteinase-mediated proteolytic cleavage. International Journal of Oncology, 52, 379-388. https://doi.org/10.3892/ijo.2017.4221
MLA
Hira-Miyazawa, M., Nakamura, H., Hirai, M., Kobayashi, Y., Kitahara, H., Bou-Gharios, G., Kawashiri, S."Regulation of programmed-death ligand in the human head and neck squamous cell carcinoma microenvironment is mediated through matrix metalloproteinase-mediated proteolytic cleavage". International Journal of Oncology 52.2 (2018): 379-388.
Chicago
Hira-Miyazawa, M., Nakamura, H., Hirai, M., Kobayashi, Y., Kitahara, H., Bou-Gharios, G., Kawashiri, S."Regulation of programmed-death ligand in the human head and neck squamous cell carcinoma microenvironment is mediated through matrix metalloproteinase-mediated proteolytic cleavage". International Journal of Oncology 52, no. 2 (2018): 379-388. https://doi.org/10.3892/ijo.2017.4221