Hypoxia and acidity regulate immune checkpoint molecule and IFN-β expression in non-small cell lung cancer cell lines

Abstract

Purpose

Non-small cell lung cancer (NSCLC) is one of the most lethal tumors in humans. Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the treatment of patients with advanced diseases. Tumor microenvironment conditions like hypoxia and low pH may compromise the efficacy of ICIs.

Materials and methods

We report the effect of hypoxia and acidity on the expression levels of the major checkpoint molecules, namely PD-L1, CD80, and CD47, in the A549 and H1299 NSCLC cell lines.

Results

Hypoxia induces PD-L1 protein and mRNA expression, represses CD80 mRNA levels, and enhances IFNβ protein expression. An opposite effect was noticed when cells were exposed to acidic conditions. Hypoxia-induced the CD47 molecule at protein and mRNA levels. It is concluded that hypoxia and acidity are important regulators of the expression of PD-L1 and CD80 immune checkpoint molecules. Acidity contributes to the suppression of the interferon type I pathway.

Conclusions

These findings suggest that hypoxia and acidity assist cancer cells in the escape from immune surveillance through direct effects on cancer cells’ ability to present immune checkpoint molecules and release type I interferons. Targeting hypoxia and acidity may enhance the activity of ICIs in NSCLC.

Keywords:

• Non-small cell lung cancer
• PD-L1
• CD80
• IFN-β
• hypoxia
• acidity

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This research is funded in the context of the project “Tumor microenvironment in lung cancer and its effect on immune response repression” (MIS 5050187) under the call for proposals “Researchers’ support with an emphasis on young researchers- 2nd Cycle). The project is co-financed by Greece and the European Union (European Social Fund- ESF) by the Operational Programme Human Resources Development, Education and Lifelong Learning 2014–2020. The Democritus University of Thrace Special Account, Project No. 81006 (Department of Medicine) supported the purchase of consumables.