Elevated cellular PD1/PD-L1 expression confers acquired resistance to cisplatin in small cell lung cancer cells

Fei Yan, Jiuxia Pang, Yong Peng, Julian R Molina, Ping Yang, Shujun Liu

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Abstract

Although small cell lung cancer (SCLC) is highly responsive to chemotherapies (e.g., cisplatin- etoposide doublet), virtually almost all responsive SCLC patients experience disease recurrence characterized by drug resistance. The mechanisms underlying cisplatin resistance remain elusive. Here we report that cell-intrinsic expression of PD1 and PD-L1, two immune checkpoints, is required for sustained expansion of SCLC cells under cisplatin selection. Indeed, PD1 and PD-L1 were expressed at a higher level in lung cancer cell lines, tumor tissues, and importantly, in SCLC cells resistant to cisplatin (H69R, H82R), when compared to respective controls. Genetic abrogation of PD1 and PD-L1 in H69R and H82R cells decreased their proliferation rate, and restored their sensitivity to cisplatin. Mechanistically, PD-L1 upregulation in H69R and H82R cells was attributed to the overexpression of DNA methyltransferase 1 (DNMT1) or receptor tyrosine kinase KIT, as knockdown of DNMT1 or KIT in H69R and H82R cells led to PD-L1 downregulation. Consequently, combined knockdown of PD-L1 with KIT or DNMT1 resulted in more pronounced inhibition of H69R and H82R cell growth. Thus, cell intrinsic PD1/PD-L1 signaling may be a predictor for poor efficacy of cisplatin treatment, and targeting the cellular PD1/PD-L1 axis may improve chemosensitization of aggressive SCLC.

Original languageEnglish (US)
Article numbere0162925
JournalPLoS One
Volume11
Issue number9
DOIs
StatePublished - Sep 1 2016

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cisplatin
Small Cell Lung Carcinoma
lung neoplasms
Cisplatin
Cells
Methyltransferases
cells
methyltransferases
DNA
Chemotherapy
Receptor Protein-Tyrosine Kinases
Cell growth
Etoposide
neoplasm cells
Tumors
Tumor Cell Line
Drug Resistance
Tissue
relapse
drug resistance

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Elevated cellular PD1/PD-L1 expression confers acquired resistance to cisplatin in small cell lung cancer cells. / Yan, Fei; Pang, Jiuxia; Peng, Yong; Molina, Julian R; Yang, Ping; Liu, Shujun.

In: PLoS One, Vol. 11, No. 9, e0162925, 01.09.2016.

Research output: Contribution to journalArticle

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