ATP/P2X7 axis modulates myeloid-derived suppressor cell functions in neuroblastoma microenvironment

Area of Science:

• Oncology
• Immunology
• Biochemistry

Background:

• The tumor microenvironment (TME) in solid tumors, including neuroblastoma (NB), is rich in extracellular adenosine and adenosine triphosphate (ATP).
• Extracellular ATP's effects on tumor and immune cells are often mediated by the P2X7 receptor (P2X7R).
• The role of the ATP/P2X7R axis in modulating myeloid-derived suppressor cells (MDSCs) within the NB TME is not well understood.

Purpose of the Study:

• To determine if extracellular ATP is present in the NB microenvironment.
• To investigate if MDSCs express functional P2X7R.
• To analyze how the ATP/P2X7R axis influences MDSC functions in NB.

Main Methods:

• Detection of extracellular ATP in NB tumor samples.
• Flow cytometry analysis of MDSC populations (CD11b+/Gr-1+) and their subtypes (monocytic MDSCs - M-MDSCs, granulocytic MDSCs - G-MDSCs).
• Assessment of P2X7R expression and functionality on MDSCs, including reactive oxygen species (ROS), arginase-1 (ARG-1), and transforming growth factor-β1 (TGF-β1) production.

Main Results:

• Extracellular ATP levels in the NB TME correlated positively with tumor progression.
• NB-bearing mice showed increased percentages of CD11b+/Gr-1+ cells compared to healthy controls.
• M-MDSCs exhibited higher levels of ROS, ARG-1, and TGF-β1, and potently stimulated tumor growth compared to G-MDSCs.
• P2X7R was found on the plasma membrane of M-MDSCs, associated with increased ARG-1, TGF-β1, and ROS production, but surprisingly uncoupled from cytotoxicity.

Conclusions:

• Extracellular ATP is a significant component of the neuroblastoma microenvironment, increasing with tumor progression.
• The ATP/P2X7R axis plays a crucial role in enhancing the immunosuppressive functions of monocytic MDSCs in neuroblastoma.
• This study elucidates a novel mechanism by which the ATP-rich tumor microenvironment promotes immune evasion and tumor progression in neuroblastoma.