# A small-molecule P2RX7 activator promotes anti-tumor immune responses and sensitizes lung tumor to immunotherapy

## TL;DR

A new molecule activates immune responses in lung cancer and improves immunotherapy effectiveness in mice.

## Contribution

HEI3090, a P2RX7 activator, enhances anti-tumor immunity and sensitizes lung tumors to immunotherapy.

## Key findings

- HEI3090 promotes IL-18 production and IFN-γ by immune cells in tumors.
- Combining HEI3090 with αPD-1 treatment leads to complete tumor regression in 80% of mice.
- Cured mice are protected against tumor re-challenge via CD8-dependent immunity.

## 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.

A limited percentage of patients with non-small cell lung cancer respond to immunotherapy. Here the authors show that HEI3090, a chemical positive modulator of the purinergic P2RX7 receptor, promotes IL-18 mediated anti-tumor immune responses and sensitizes lung cancer to anti-PD-1 therapy in preclinical models.