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

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.

DOI: 10.1016/j.lungcan.2017.04.010

Cite this paper

@article{Suda2017TherapyinducedED, title={Therapy-induced E-cadherin downregulation alters expression of programmed death ligand-1 in lung cancer cells.}, author={Kenichi Suda and Leslie M Rozeboom and Christopher J. Rivard and Hui Yu and Kim E. Ellison and Mary Ann C Melnick and Trista K. Hinz and Daniel C.F. Chan and Lynn E. Heasley and Katerina A Politi and Tetsuya Mitsudomi and Fred R . Hirsch}, journal={Lung cancer}, year={2017}, volume={109}, pages={1-8} }