Regulation of PD-L1 expression in a high-grade invasive human oral squamous cell carcinoma microenvironment

Hirai, Mariko; Kitahara, Hiroko; Kobayashi, Yutaka; Kato, Koroku; Bou‐Gharios, George; Nakamura, Hiroyuki; Kawashiri, Shin‐ya

doi:10.3892/ijo.2016.3785

Cited by 66 publications

(76 citation statements)

References 50 publications

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“…Many recent studies have highlighted the critical role of PD-L1 in regulating the biological functions of cancer cells themselves, including cell proliferation, migration, metastasis, chemo/radio-resistance, and the promotion of epithelial to mesenchymal transition [9,10,18,21,23,[30][31][32]. It has been suggested that signal pathways such as JAK/ STAT1/IRF-1, MEK/ERK/STAT1 and PKD2 etc.…”

Section: Discussionmentioning

confidence: 99%

PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer

Chen

Xiong

et al. 2017

Cell Physiol Biochem

100

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Background/Aims: PD-L1 (Programmed cell death 1 ligand 1, PD-L1), an essential immune checkpoint molecule in the tumor microenvironment, is an important target for cancer immunotherapy. We have previously reported that its expression in human gastric and esophageal cancer tissues is significantly associated with cancer progression and patients' postoperative prognoses. Its expression in cancer cells is well known to inhibit the T cellmediated anti-tumor response, and this mechanism of action has been targeted for cancer immunotherapy. As of now, the autonomous effect of PD-L1 on cancer cells is not well understood, thus our present study aimed to examine the role of PD-L1 intervention in cellular biological functions, especially epithelial to mesenchymal transition (EMT), of the human esophageal cancer cell line, Eca-109 cells. Methods: Immunohistochemistry assay was used to investigate the correlation between expression of PD-L1 and EMT markers in human esophageal cancer tissues. Intervention of PD-L1 by using RNAi and over-expression methods were used to study the role of PD-L1 in regulation of biological behaviors and EMT in Eca-109 cells. Results: Our clinical and pathological data demonstrated that tumor samples in the EMT positive subgroup had higher PD-L1 expression than those in the EMT negative subgroup. By manipulating PD-L1 expression in Eca-109 cells either through ablation or overexpression of wild type and the cytoplasmic domain-truncated mutant, we demonstrated that PD-L1 expression significantly promoted the cell viability, migration and EMT phenotype. Furthermore, our study also indicated that PD-1 fusion protein mediated stimulation of PD-L1 and the cytoplasmic domain of PD-L1 played a critical role in promoting EMT phenotype of Eca-109 cells, thereby suggesting that PD-1 receptor usually by triggering the reverse signaling can effect PD-L1 mediated regulation of esophageal cancer cell response. Conclusion: Our present study reveals a tumor cell-autonomous role of PD-L1 signaling in promoting EMT in human esophageal cancer.L. Chen and Y. Xiong contributed equally to this work.

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Section: Discussionmentioning

confidence: 99%

PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer

Chen

Xiong

et al. 2017

Cell Physiol Biochem

100

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“…Upregulation of PD‐L1 in the TME predicts poor prognosis in patients with cancer . Blocking the PD‐1/PD‐L1 pathway has shown promising results in several carcinomas . In this study, we showed that the TME highly expressed PD‐L1 after tumor vaccine therapy.…”

Section: Discussionmentioning

confidence: 53%

“…SA‐IL‐2‐modified vaccine monotherapy increased the proportion of CD4 + Foxp3 + T cells. The high frequency of Tregs could decrease the number of mature DC and disrupt the interactions between DC and T cells by direct contact or by changing the immune microenvironment . Interestingly, adding PD‐1 blockade to SA‐IL‐2‐modified vaccine therapy could reduce the proportion of CD4 + Foxp3 + T cells.…”

Section: Discussionmentioning

confidence: 99%

Combination immunotherapy with interleukin‐2 surface‐modified tumor cell vaccine and programmed death receptor‐1 blockade against renal cell carcinoma

Zhang

Shi

et al. 2018

Cancer Science

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Immunotherapy may be an effective way to prevent postoperative recurrence of renal cell carcinoma. Streptavidin‐interleukin‐2 (SA‐IL‐2) surface‐modified tumor cell vaccine developed through our protein‐anchor technology could induce specific antitumor T‐cell responses, but this immunotherapy cannot completely eradicate the tumor. These effector T cells highly expressed programmed death receptor‐1 (PD‐1), and the expression of programmed death ligand‐1 (PD‐L1) in the tumor environment also was upregulated after SA‐IL‐2‐modified vaccine therapy. PD‐1/PD‐L1 interaction promotes tumor immune evasion. Adding PD‐1 blockade to SA‐IL‐2‐modified vaccine therapy increased the number of CD4+, CD8+ and CD8+interferon‐γ+ but not CD4+Foxp3+ T cells. PD‐1 blockade could rescue the activity of tumor‐specific T lymphocytes induced by the SA‐IL‐2‐modified vaccine. Combination therapy delayed tumor growth and protected mice against a second Renca cells but not melanoma cells challenge. Taken together, PD‐1 blockade could reverse immune evasion in the treatment with SA‐IL‐2‐modified vaccine, and eventually induce a stronger specific antitumor immune response against renal cell carcinoma.

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“…PD‐1/PD‐L1 interactions inhibit the functions and proliferation of activated T lymphocytes . Interruption of the PD‐1/PD‐L1 pathway is currently being investigated and has shown promising results in several carcinomas . Upregulation of PD‐L1 in the TME predicts poor survival in patients with cancer .…”

Section: Discussionmentioning

confidence: 99%

PD‐1 blockade enhances the antitumor efficacy of GM‐CSF surface‐modified bladder cancer stem cells vaccine

Shi

Zhang

et al. 2017

Intl Journal of Cancer

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Eliminating cancer stem cells (CSCs) is a key issue in eradicating tumor. The streptavidin-granulocyte-macrophage-colony stimulating factor (SA-GM-CSF) surface-modified bladder CSCs vaccine previously developed using our protein-anchor technology could effectively induce specific immune response for eliminating CSCs. However, program death receptor-1 (PD-1)/program death ligand 1 (PD-L1) signaling in tumor microenvironment results in tumor-adaptive immune resistance. Although the CSCs vaccine could increase the number of CD8 T cells, a part of these CD8 T cells expressed PD-1. Moreover, the CSCs vaccine upregulated the PD-L1 expression of tumor cells, resulting in immune resistance. Adding PD-1 blockade to the CSCs vaccine therapy increased the population of CD4 , CD8 and CD8 IFN-γ but not CD4 Foxp3 T cells and induced the highest production of IFN-γ. PD-1 blockade could effectively enhance the functions of tumor-specific T lymphocytes generated by the CSCs vaccine. This combination therapy improved the cure rate among mice and effectively protected the mice against a second CSCs cell challenge, but not a RM-1 cell challenge. These results indicate that PD-1 blockade combined with the GM-CSF-modified CSCs vaccine effectively induced a strong and specific antitumor immune response against bladder cancer.

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Regulation of PD-L1 expression in a high-grade invasive human oral squamous cell carcinoma microenvironment

Cited by 66 publications

References 50 publications

PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer

PD-L1 Expression Promotes Epithelial to Mesenchymal Transition in Human Esophageal Cancer

Combination immunotherapy with interleukin‐2 surface‐modified tumor cell vaccine and programmed death receptor‐1 blockade against renal cell carcinoma

PD‐1 blockade enhances the antitumor efficacy of GM‐CSF surface‐modified bladder cancer stem cells vaccine

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