Abstract
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.
Highlights
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
HEI3090 action required the expression of P2RX7, since HEK cells transfected with empty plasmid showed no increase in intracellular calcium concentration (Fig. 1c)
We showed that HEI3090 required the expression of P2RX7, since its effect was lost in splenocytes isolated from p2rx7−/− mice
Summary
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. Faculty of Chemistry, Despite new biological insights and recent therapeutic advances, many tumors remain resistant to treatments, leading to premature death of the patient. This is true for lung cancer, which is the leading cause of cancer death for men and women worldwide. Activation of P2RX7 by high doses of extracellular ATP (eATP) leads to Na+ and Ca2+ influx, and, after prolonged activation, to the opening of a larger conductance membrane pore One consequence of this large pore opening, a unique characteristic of P2RX7, is to induce cell death in eATP rich microenvironments. Regulatory T cells (Treg) are highly sensitive to
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
