Abstract
Tumor microenvironment of solid tumors is characterized by a strikingly high concentration of adenosine and ATP. Physiological significance of this biochemical feature is unknown, but it has been suggested that it may affect infiltrating immune cell responses and tumor progression. There is increasing awareness that many of the effects of extracellular ATP on tumor and inflammatory cells are mediated by the P2X7 receptor (P2X7R). Aim of this study was to investigate whether: (i) extracellular ATP is a component of neuroblastoma (NB) microenvironment, (ii) myeloid-derived suppressor cells (MDSCs) express functional P2X7R and (iii) the ATP/P2X7R axis modulates MDSC functions. Our results show that extracellular ATP was detected in NB microenvironment in amounts that increased in parallel with tumor progression. The percentage of CD11b+/Gr-1+ cells was higher in NB-bearing mice compared with healthy animals. Within the CD11b/Gr-1+ population, monocytic MDSCs (M-MDSCs) produced higher levels of reactive oxygen species (ROS), arginase-1 (ARG-1), transforming growth factor-β1 (TGF-β1) and stimulated more potently in vivo tumor growth, as compared with granulocytic MDSCs (G-MDSCs). P2X7R of M-MDSCs was localized at the plasma membrane, coupled to increased functionality, upregulation of ARG-1, TGF-β1 and ROS. Quite surprisingly, the P2X7R in primary MDSCs as well as in the MSC-1 and MSC-2 lines was uncoupled from cytotoxicity. This study describes a novel scenario in which MDSC immunosuppressive functions are modulated by the ATP-enriched tumor microenvironment.
Highlights
Tumor microenvironment is a complex milieu enriched with molecules released by malignant and inflammatory cells, including cytokines, chemokines, growth factors and purines.[5]
Our results demonstrate that P2X7 receptor (P2X7R) expression and function are different in either granulocytic or monocytic myeloid-derived suppressor cells (MDSCs) (G- or M-MDSCs), allowing a divergent modulation of the two different MDSC subsets by extracellular ATP
In order to detect extracellular ATP in NB microenvironment, the murine NB NXS2 cell line was stably transfected with the plasma membrane luciferase probe, and intravenously injected into immunocompetent syngeneic A/J mice
Summary
Tumor microenvironment is a complex milieu enriched with molecules released by malignant and inflammatory cells, including cytokines, chemokines, growth factors and purines.[5]. Extracellular ATP and adenosine (Ado) are potent modulators of immune cell responses and cytokine release and support cancer cell growth.[6,7,8]. ATP, a well-known danger signal molecule with proinflammatory properties, is released by virtually all cell types.[5]. Once accumulated in the tumor microenvironment, ATP exerts effects that are either beneficial or detrimental to the host depending on: (i) its concentration, (ii) the P2 receptor (P2R) subtypes and (iii) the expression levels of nucleotidedegrading enzymes, such as CD39 and CD73, in immune, tumor and stromal cells.[5] CD39 and CD73 convert ATP into. That in turn causes immunosuppression and may promote cancer cell growth.[9,10,11] By directly interacting with
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