Ectonucleotidase CD73 and CD39 expression in non-small cell lung cancer relates to hypoxia and immunosuppressive pathways.

Autor: Giatromanolaki A; Department of Pathology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece. Electronic address: agiatrom@med.duth.gr., Kouroupi M; Department of Pathology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece., Pouliliou S; Department of Radiotherapy/Oncology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece., Mitrakas A; Department of Radiotherapy/Oncology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece., Hasan F; Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus Dragana, 68100 Alexandroupolis, Greece., Pappa A; Department of Molecular Biology and Genetics, Democritus University of Thrace, University Campus Dragana, 68100 Alexandroupolis, Greece., Koukourakis MI; Department of Radiotherapy/Oncology, Medical School, Democritus University of Thrace, Alexandroupolis, Greece.
Jazyk: angličtina
Zdroj: Life sciences [Life Sci] 2020 Oct 15; Vol. 259, pp. 118389. Date of Electronic Publication: 2020 Sep 06.
DOI: 10.1016/j.lfs.2020.118389
Abstrakt: Aims: Adenosine triphosphate (ATP) is released at a high concentration in the tumor microenvironment. The overexpression of ectonucleotidases in non-small-cell lung cancer (NSCLC), metabolizing ΑΤP to the immunosuppressive adenosine, is studied.
Materials and Methods: We examined the expression of the ectonucleotidases CD73 and CD39 in NSCLC in parallel with immunological parameters and markers of hypoxia and anaerobic metabolism. In vitro experiments with A549 and H1299 lung cancer cell lines were also conducted.
Results: CD73 and CD39 were not expressed by normal bronchial and alveolar epithelium. In contrast, these were overexpressed by cancer cells, cancer-associated fibroblasts (CAFs), and tumor-infiltrating lymphocytes (TILs). High CD73 cancer cell expression was directly linked with lactate dehydrogenase LDH5 and with hypoxia-inducible factor HIF1α expression by cancer cells. The expression of CD39 by CAFs was directly linked with PD-L1 expression by cancer cells. A significant abundance of FOXP3+ and PD-1+ TILs was noted in tumors with high CD73 and CD39 stroma expression. In in vitro experiments, hypoxia and acidity induced CD73 mRNA and protein levels in cancer cell lines. Exposure of cancer cell lines to adenosine induced the expression of PD-L1 and LDHA mRNA and protein levels.
Conclusion: Ectonucleotidases are up-regulated in cancer cells, CAFs, and TILs in lung tumors. Such overexpression is linked with regulatory TIL-phenotype and PD-L1 up-regulation by cancer cells. Overexpression of LDH5 is up-regulated by adenosine, creating a vicious cycle, as the high amounts of ATP produced by LDH5-mediated anaerobic glycolysis promote the production of adenosine by a tumor microenvironment rich in ectonucleotidases.
Competing Interests: Declaration of competing interest There are no conflicts of interest to report.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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