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

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.

Methylseleninic Acid Sensitizes Ovarian Cancer Cells to T-Cell Mediated Killing by Decreasing PDL1 and VEGF Levels

“…Consistently our results also show an upregulation of MMP9, MMP13 and MMP19 in response to MSA. MMPs have recently been shown to degrade PDL1 ( 20 ), thus the decreased protein levels of PDL1 after MSA treatment of CP70 cells found in the current study, may likely be explained via the induction of MMPs that subsequently degrade PDL1. A further study is warranted to confirm if the mechanism by which MSA downregulates PDL1 is via MMPs.…”

“…The downregulation of PDL1 however did not occur at the transcriptional level as the mRNA expression of PDL1 was drastically increased upon MSA treatment (Figure 3B ). To further understand the mechanism of PDL1 downregulation, the expression of matrix metalloproteineases (MMP9, MMP13, and MMP 19) were analyzed, as MMPs have been reported to degrade PDL1 ( 20 ). All the three MMP's were significantly upregulated in response to MSA (Figure 3C ).…”

Metalloproteinases and their roles in human cancer

“…Recombinant MMP‐13 and MMP‐7 were shown to degrade intact purified PD‐L1 without observation of low‐molecular‐weight fragments suggesting that the degradation may be occurring at the PD‐1 binding domain. In addition, treatment of human squamous cell carcinoma cells OSC‐20 with a specific inhibitor of MMP‐13 (CL82198) restored PD‐L1 expression suggesting that the shedding/cleavage of PD‐L1 by MMP‐13 may play a role in the protective effect against invasion and metastasis (Hira‐Miyazawa et al, ). Recently, it was also shown that treatment with anti‐PD‐L1 antibody resulted in a decrease of both mRNA and protein levels of MMP‐2 and MMP‐9 in pancreatic cancer and liver metastases in a syngeneic pancreatic cancer mouse model (Fig.…”

Exosomal PD-L1: New Insights Into Tumor Immune Escape Mechanisms and Therapeutic Strategies

“…Notably, soluble PD-L1 may be generated from ectodomain shedding mediated by either matrix metalloproteinases (MMPs) or a disintegrin and metalloproteases (ADAMs). Additionally, soluble PD-L1 may be produced by alternative splice variants omitting transmembrane domain (Dezutter-Dambuyant et al, 2016;Hira-Miyazawa et al, 2018;Aguirre et al, 2020;Orme et al, 2020;Romero et al, 2020). Although soluble PD-L1 is found in human serum and is regarded as a liquid biopsy predictor, whether soluble PD-L1 can deliver a regulatory signal through PD-1 remains elusive (Gu et al, 2018;Takeuchi et al, 2018;Abu Hejleh et al, 2019;Asanuma et al, 2020).…”