Abstract 6326: Reshaping immune lung populations to inhibit pulmonary fibrosis and cancer by activation of purinergic receptor P2RX7

Abstract

Abstract Lung cancer is the most prevalent cancer worldwide with high mortality rate despite recent advances in therapies. Not only is fibrosis a major hallmark of lung cancer, it is also a risk factor for lung cancer development (mainly non-small cell lung cancer). In fact, patients diagnosed with idiopathic pulmonary fibrosis (IPF) are very likely to develop lung cancer. However, treatment and outcome of lung cancer patients with IPF is different than those without IPF despite their common genetic, molecular, cellular and immune properties. New therapeutic strategies are needed for improving outcome of patients bearing both diseases. To address this, we proposed that boosting the activation of P2RX7 with a positive modulator (HEI3090) would be a novel strategy to fight lung cancer. P2RX7 is a purinergic receptor activated by high extracellular ATP levels found in inflamed and tumor sites. It has anti-tumor and immunomodulatory properties by its ability to induce cell death and the release of IL-1b and IL-18. We showed previously that HEI3090 inhibits lung tumor growth by triggering an anti-tumor immune response that relies on IL-18. Indeed, HEI3090-release of IL-18 enhanced the cytotoxicity of NK cells and favored a Th1-biased immune response. Given that lung fibrosis is partly driven by inflammation with a dysregulated Th1/Th2/Th17 ratios and given the ability of HEI3090 to favor a Th1-biased immune response, we wondered if HEI3090 was able to inhibit fibrosis. To do so, we used the bleomycin mouse model where we show that activation of P2RX7 with HEI3090 inhibits lung fibrosis. HEI3090 targets P2RX7-expressing immune cells, decreases lung inflammation and favors an anti-fibrotic immune signature. Indeed, HEI3090 promotes the production of IFN-g by T cells and decreases pro-fibrotic IL-17A release by Th17 cells. Moreover, production of TGF-b, the key cytokine driving fibrosis, was greatly reduced in immune cells in HEI3090-treated mice. The antifibrotic effect of HEI3090 seems to rely on an increase of IL-18, known to induce the production of IFN-g by T cells. Overall, we show that reshaping lung immune phenotype by activation of P2RX7 is a promising strategy in lung fibrosis. HEI3090’s effect on cancer-related fibrosis is ongoing on a Kras mouse model. We highlight a new therapeutic strategy for patients with IPF that would ameliorate treatment and outcome of patients with both lung cancer and fibrosis Citation Format: Serena Janho dit Hreich, Alina Ghinet, Valérie Vouret-Craviari. Reshaping immune lung populations to inhibit pulmonary fibrosis and cancer by activation of purinergic receptor P2RX7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6326.