Cytokine-Induced Killer Cells Express CD39, CD38, CD203a, CD73 Ectoenzymes and P1 Adenosinergic Receptors

Alberto L Horenstein; Antonella Chillemi; Roberta Zini; Valeria Quarona; Nicoletta Bianchi; Rossella Manfredini; Roberto Gambari; Fabio Malavasi; Davide Ferrari

doi:10.3389/fphar.2018.00196

Cytokine-Induced Killer Cells Express CD39, CD38, CD203a, CD73 Ectoenzymes and P1 Adenosinergic Receptors

Front Pharmacol. 2018 Apr 20:9:196. doi: 10.3389/fphar.2018.00196. eCollection 2018.

Authors

Alberto L Horenstein¹, Antonella Chillemi¹, Roberta Zini², Valeria Quarona¹, Nicoletta Bianchi³, Rossella Manfredini², Roberto Gambari³, Fabio Malavasi¹, Davide Ferrari³

Affiliations

¹ Laboratory of Immunogenetics and CeRMS, Department of Medical Sciences, University of Torino, Torino, Italy.
² Centre for Regenerative Medicine "Stefano Ferrari," Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
³ Department of Life Science and Biotechnology, Section of Microbiology and Applied Pathology, University of Ferrara, Ferrara, Italy.

Abstract

Cytokine-induced killer (CIK) cells, a heterogeneous T cell population obtained by in vitro differentiation of peripheral blood mononuclear cells (PBMC), represent a promising immunological approach in cancer. Numerous studies have explored the role of CD38, CD39, CD203a/PC-1, and CD73 in generating extracellular adenosine (ADO) and thus in shaping the tumor niche in favor of proliferation. The findings shown here reveal that CIK cells are able to produce extracellular ADO via traditional (CD39/CD73) and/or alternative (CD38/CD203a/CD73 or CD203a/CD73) pathways. Transcriptome analysis showed the mRNA expression of these molecules and their modulation during PBMC to CIK differentiation. When PBMC from normal subjects or cancer bearing patients were differentiated into CIK cells under normoxic conditions, CD38 and CD39 were greatly up-regulated while the number of CD203a, and CD73 positive cells underwent minor changes. Since hypoxic conditions are often found in tumors, we asked whether CD39, CD38, CD203a, and CD73 expressed by CIK cells were modulated by hypoxia. PBMC isolated from cancer patients and differentiated into CIK cells in hypoxic conditions did not show relevant changes in CD38, CD39, CD73, CD203a, and CD26. CIK cells also expressed A₁, A_2A, and A_2B ADO receptors and they only underwent minor changes as a consequence of hypoxia. The present study sheds light on a previously unknown functional aspect of CIK cells, opening the possibility of pharmacologically modulated ADO-generating ectoezymes to improve CIK cells performance.

Keywords: CD203a/PC-1; CD38; CD39; CD73; CIK; P1 receptors; adenosine; hypoxia.