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Lung Cancer. 2017 Jul;109:1-8. doi: 10.1016/j.lungcan.2017.04.010. Epub 2017 Apr 19.

Therapy-induced E-cadherin downregulation alters expression of programmed death ligand-1 in lung cancer cells.

Author information

1
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, 12801 E. 17th Ave, RC-1 South, Aurora, CO 80045, USA; Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama 589-0014, Japan. Electronic address: ascaris@surg2.med.kyushu-u.ac.jp.
2
Division of Medical Oncology, University of Colorado Anschutz Medical Campus, 12801 E. 17th Ave, RC-1 South, Aurora, CO 80045, USA.
3
Department of Pathology, Yale University School of Medicine,310 Cedar St., New Haven, CT 06520, USA.
4
Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, 12801 E. 17th Ave, RC-1 South, Aurora, CO 80045, USA.
5
Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama 589-0014, Japan.

Abstract

OBJECTIVES:

Immunotherapy that targets the programmed death-1/programmed death-ligand 1 (PD-L1) axis has been approved for treatment of non-small cell lung cancer (NSCLC) patients in many countries. However, our current understanding of the role of immunotherapies on NSCLC patients with epidermal growth factor receptor (EGFR) mutation, following acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs), is so far unclear. Especially, there is little data on if each acquired resistance mechanism to EGFR-TKIs alters PD-L1 expression status which is employed as an important predictive biomarker for PD-1/PD-L1 targeting agents.

MATERIALS AND METHODS:

Lung cancer cell lines (HCC827, HCC4006, PC9, H1975, H358, SW900, and H647) and their daughter cells that acquired resistance to EGFR-TKIs or cytotoxic drugs (cisplatin or vinorelbine) were examined. PD-L1 expression was analyzed by immunohistochemistry, immunoblotting, and/or fluorescent imaging. Published microarray data were also employed to evaluate our findings.

RESULTS AND CONCLUSION:

We found correlations between therapy-induced E-cadherin downregulation and decreased PD-L1 expression using our cell lines and published microarray data. ShRNA mediated E-cadherin knockdown decreased PD-L1 expression in parental cells, and dual immunofluorescent staining of E-cadherin and PD-L1 suggests co-localization of both molecules. We also observed marked downregulation of PD-L1 in cells with E-cadherin downregulation after chronic treatment with vinorelbine. These results indicate a correlation between therapy-induced E-cadherin downregulation and decreased PD-L1 expression, highlighting the importance of re-biopsy after acquisition of resistance to EGFR-TKIs, not only for the evaluation of resistance mechanisms but also for the determination of PD-L1 expression status.

KEYWORDS:

Acquired resistance; EGFR mutation; EGFR-TKIs; Epithelial to mesenchymal transition (EMT); Erlotinib; Immunotherapy

PMID:
28577937
PMCID:
PMC6174882
DOI:
10.1016/j.lungcan.2017.04.010
[Indexed for MEDLINE]
Free PMC Article

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