Modulation of the PD-1/PD-L1 immune checkpoint axis during inflammation-associated lung tumorigenesis

Sreekanth Chanickal Narayanapillai, Yong Hwan Han, Jung Min Song, Manaye Ebabu Kebede, Pramod Upadhyaya, Fekadu Kassie

Research output: Contribution to journalArticlepeer-review

11 Scopus citations


Chronic obstructive pulmonary disease (COPD) is a significant risk factor for lung cancer. One potential mechanism through which COPD contributes to lung cancer development could be through generation of an immunosuppressive microenvironment that allows tumor formation and progression. In this study, we compared the status of immune cells and immune checkpoint proteins in lung tumors induced by the tobacco smoke carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) or NNK + lipopolysaccharide (LPS), a model for COPD-associated lung tumors. Compared with NNK-induced lung tumors, NNK+LPS-induced lung tumors exhibited an immunosuppressive microenvironment characterized by higher relative abundances of PD-1+ tumor-associated macrophages, PD-L1+ tumor cells, PD-1+ CD4 and CD8 T lymphocytes and FOXP3+ CD4 and CD8 T lymphocytes. Also, these markers were more abundant in the tumor tissue than in the surrounding 'normal' lung tissue of NNK+LPS-induced lung tumors. PD-L1 expression in lung tumors was associated with IFNγ/STAT1/STAT3 signaling axis. In cell line models, PD-L1 expression was found to be significantly enhanced in phorbol-12-myristate 13-acetate activated THP-1 human monocytes (macrophages) treated with LPS or incubated in conditioned media (CM) generated by non-small cell lung cancer (NSCLC) cells. Similarly, when NSCLC cells were incubated in CM generated by activated THP-1 cells, PD-L1 expression was upregulated in EGFR- and ERK-dependent manner. Overall, our observations indicate that COPD-like chronic inflammation creates a favorable immunosuppressive microenvironment for tumor development and COPD-associated lung tumors might show a better response to immune checkpoint therapies.

Original languageEnglish (US)
Pages (from-to)1518-1528
Number of pages11
Issue number11
StatePublished - Nov 13 2020

Bibliographical note

Funding Information:
This study was financially supported by National Institutes of Health/National Cancer Institute grant (RO1CA166615-01 to F.K.).

Publisher Copyright:
© 2020 The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email:

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural


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