Role of P2X7 receptor in tumor-host interaction

Introduction: The P2X7 receptor (P2X7R) is an ion channel belonging to the P2X purinergic family, activated by extracellular ATP. It is chiefly expressed by immune cells, such as macrophages and dendritic cells (DCs). It acts as pro-inflammatory receptor, mediating secretion of mature interleukin-1 beta (IL- 1β) and as modulator of immune response.1 Recently it has been characterized a growth-promoting activity of P2X7R especially in cancer cells.2 P2X7R is overexpressed by many malignancies2,3 and supports tumor growth2 and metastatization in vivo4. As P2X7R is involved both in tumor growth and in host immune defence, it is challenging to predict which would be the final effect of targeting P2X7R in cancer therapy. To unravel this question we induced experimental subcutaneous melanoma and lung metastatis formation in P2X7R-KO mice. Materials and methods: B16 murine melanoma cells were subcutaneously or intravenously inoculated into wild type (wt) and P2X7R-KO syngeneic C57Bl/6. Tumor mass growth was monitored by in vivo caliper measurement, while metastatic spreading was followed by total body luminometer (IVIS Lumina) thanks to cell transfection with intracellular luciferase. Pharmacological treatments were administrated as intra peritoneal injection every two days and two different P2X7R antagonists were used. Results: Tumor growth and metastatic diffusion were strongly accelerated in P2X7R-KO compared to wt mice. Immunohistochemical analysis of tumors revealed that lymphocytic and macrophagic infiltrate (CD3+ or F4/80 positive cells, respectively) was almost abrogated in P2X7R-KO mice. This inability to recruit immune cells could be due to incapacity of P2X7R-less cells to respond to stimulation by cancer cells. In line with this prediction, IL-1β content of tumors from P2X7R-KO mice was drastically reduced compared to that of wt, IL-1β release from B16-stimulated DCs of P2X7R-KO mice was neglible and chemotaxis of P2X7R-null immune cells was nearly abrogated. Conclusions: P2X7R is a non redundant factor in anti-cancer immunity. 1Rayah A et al.; Microbes Infect. 2012, 14(14):1254-62 2Adinolfi E et al.; Cancer Res. 2012, 72:2957-69 3Slater M et al. Histopathology 2004, 44(3):206-15. 4Adinolfi E et al Blood 2002, 15;99(2):706-8 5Jelassi B et al.; Oncogene 2011, 5;30(18):2108-2