Blocking P2X7-Mediated Macrophage Polarization Overcomes Treatment Resistance in Lung Cancer
Menée in vitro et in vivo, cette étude met en évidence l'intérêt de bloquer la polarisation des macrophages induite par le récepteur P2X7 pour lever la résistance thérapeutique des cellules cancéreuses du poumon
P2X7, a crucial sensor of extracellular ATP, is widely distributed in different immune cells as a potent stimulant of inflammation and immunity. P2X7 is also highly expressed in immunosuppressive cells such as tumor-associated macrophages (TAMs) and even tumor cells. However, the function and potential applications of P2X7-mediated immunosuppressive responses in tumor microenvironment remains unclear. Here, we demonstrated that P2X7 was highly expressed in TAMs and that P2X7 deficiency impaired the "M2-like" polarization of TAMs via down-regulation of STAT6 and IRF4 phosphorylation both in vivo and in vitro. P2X7 deficiency restricted the progression of urethane-induced lung carcinogenesis and Lewis lung cancer by decreasing tumor cell proliferation and angiogenesis, promoting T cell mobilization, and reversing M2-like TAM polarization. Thus, deletion or blockade of P2X7 was therapeutic for lung cancer. Furthermore, resistance to immunotherapy (anti-PD-1 antibody) and chemotherapy (cisplatin) were both overcome by co-administration of the P2X7 inhibitors O-ATP, A-438079 hydrochloride and A-740003. Therefore, our data revealed a vital role of P2X7 in tumor formation through regulating TAM polarization, suggesting the therapeutic potential of P2X7 blockade in lung cancer patients.