Blocking P2X7-Mediated Macrophage Polarization Overcomes Treatment Resistance in Lung Cancer
Juliang Qin1,2, Xiaoyu Zhang1, Binghe Tan1
1Changning Maternity and Infant Health Hospital and School of Life Sciences, Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai, China.
Abstract:
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.
Insights
Blocking P2X7, an inflammation sensor, reverses immunosuppressive tumor cell responses. This strategy shows therapeutic potential for lung cancer by inhibiting tumor growth and enhancing immunotherapy and chemotherapy effectiveness.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- P2X7 receptor (P2X7) acts as an extracellular ATP sensor, stimulating inflammation and immunity.
- P2X7 is expressed in immune cells and also in immunosuppressive cells like tumor-associated macrophages (TAMs) and tumor cells.
- The role of P2X7 in the tumor microenvironment's immunosuppressive responses is not fully understood.
Purpose of the Study:
- To investigate the function and therapeutic potential of P2X7 in lung cancer.
- To explore the role of P2X7 in regulating TAM polarization within the tumor microenvironment.
- To assess the efficacy of P2X7 blockade in combination with existing cancer therapies.
Main Methods:
- Studied P2X7 expression in TAMs.
- Utilized P2X7 deficiency models (in vivo and in vitro) to analyze TAM polarization.
- Assessed the impact of P2X7 deficiency on lung carcinogenesis and tumor progression.
- Evaluated the effects of P2X7 inhibitors (O-ATP, A-438079 hydrochloride, A-740003) in combination with anti-PD-1 antibody and cisplatin.
Main Results:
- P2X7 deficiency impaired M2-like TAM polarization by downregulating STAT6 and IRF4 phosphorylation.
- P2X7 deficiency restricted lung cancer progression by reducing tumor cell proliferation and angiogenesis, and promoting T-cell mobilization.
- P2X7 blockade, using inhibitors, overcame resistance to anti-PD-1 immunotherapy and cisplatin chemotherapy.
Conclusions:
- P2X7 plays a critical role in tumor formation by modulating TAM polarization.
- Targeting P2X7 represents a promising therapeutic strategy for lung cancer.
- Combining P2X7 inhibitors with immunotherapy or chemotherapy can enhance treatment efficacy in lung cancer patients.
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