Douguet Laetitia, Janho Dit Hreich Serena, Benzaquen Jonathan, Seguin Laetitia, Juhel Thierry, Dezitter Xavier, Duranton Christophe, Ryffel Bernhard, Kanellopoulos Jean, Delarasse Cecile, Renault Nicolas, Furman Christophe, Homerin Germain, Féral Chloé, Cherfils-Vicini Julien, Millet Régis, Adriouch Sahil, Ghinet Alina, Hofman Paul, Vouret-Craviari Valérie
Université Côte d'Azur, CNRS, INSERM, IRCAN, Nice, France.
FHU OncoAge, Nice, France.
Nat Commun. 2021 Jan 28;12(1):653. doi: 10.1038/s41467-021-20912-2.
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.
只有一小部分非小细胞肺癌（NSCLC）患者对免疫疗法有反应，这凸显了迫切需要制定治疗策略以改善患者预后。我们开发了一种嘌呤能P2RX7受体的化学正向调节剂（HEI3090），它能增强αPD-1治疗效果，从而在可移植和致癌基因诱导的小鼠模型中有效控制肺肿瘤的生长，并引发持久的抗肿瘤免疫反应。从机制上讲，该分子刺激表达P2RX7的树突状细胞产生IL-18，进而导致肿瘤内的自然杀伤细胞和CD4 T细胞产生IFN-γ。与免疫检查点抑制剂联合使用时，该分子可使80%的荷LLC肿瘤小鼠出现完全肿瘤消退。由于存在依赖CD8的保护性反应，治愈的小鼠也能免受肿瘤再次攻击。因此，小分子P2RX7激活剂联合免疫检查点抑制剂的治疗方案代表了一种可能对NSCLC有效的策略。
