Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop therapeutic strategies to improve patient outcome. We develop a chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7-expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4⁺ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor-bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a strategy that may be active against NSCLC.

The purinergic receptor P2X7 is highly expressed in immune peripheral and central cells suggesting its important role in numerous diseases characterized by inflammatory processes like cancer, or neurodegenerative pathologies in relation with modulation of the immune system. Thereby, antagonization of this receptor may be a hopeful therapeutic strategy to treat a large range of diseases. Indeed, selective P2X7 antagonists display beneficial anti-inflammatory, analgesic, and in some cases, anticancer properties. This article will review the involvement of P2X7 in the immune system, the update of P2X7 antagonists series since 2009 and their promising therapeutic potential for the treatment of several immune- related diseases.