Journal
CANCER IMMUNOLOGY RESEARCH
Volume 8, Issue 11, Pages 1426-1439Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-20-0123
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Funding
- National Key R&D Program of China [2018YFA0507001]
- National Natural Science Foundation of China [81672811, 31770969, 81871250, 81902892]
- Shanghai Super Postdoctoral Incentive Program
- China Postdoctoral Science Foundation [2018M640364]
- Shanghai Sailing Program [19YF1414400]
- Innovation Program of Shanghai Municipal Education Commission [2017-01-07-00-05-E00011]
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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 (TAM) and even tumor cells. However, the function and potential applications of P2X7-mediated immunosuppressive responses in the tumor microenvironment remain unclear. Here, we demonstrated that P2X7 was highly expressed in TAMs and that P2X7 deficiency impaired the M2-like polarization of TAMs via downregulation 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 both immunotherapy (anti-PD-1 antibody) and chemotherapy (cisplatin) was overcome by coadministration 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 patients with lung cancer.
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