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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38 Scopus citations

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 2016

Bibliographical note

Funding Information:
This work was supported in part by National Cancer Institute (Bethesda, MD) grants R01CA149623 (SL), R21CA155915 (SL) and Hormel Institute Foundation 4592336 (SL).

Publisher Copyright:
© 2016 Yan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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