肿瘤细胞治疗研究
英文原题：Extracellular ATP-P2RY2 signaling drives intratumoral prostaglandin E2 accumulation and adaptive resistance to immunotherapy in solid tumors.
细胞外 ATP（eATP）在肿瘤微环境（TME）中蓄积，其代谢产物腺苷被认为可促进免疫抑制通路。
肿瘤微环境（TME）中细胞外ATP（eATP）积累，其代谢产物腺苷被认为可促进免疫抑制通路。我们发现，免疫治疗会进一步提高TME中的eATP浓度。eATP可直接通过肿瘤细胞上的嘌呤能受体P2RY2传递信号，不依赖其代谢产物而抑制T细胞功能。从机制上看，eATP-P2RY2信号驱动环氧合酶（COX）-1和COX-2表达，并导致下游前列腺素E2（PGE2）积累。遗传敲除或药理学抑制P2RY2可降低瘤内基线PGE2水平，阻止治疗诱导的PGE2积累，改变TME免疫浸润，恢复抗肿瘤T细胞应答，并克服对免疫检查点阻断、CAR-T和TCR-T疗法的耐药。P2RY2拮抗性单克隆抗体重现了体内治疗获益，并在体外增强人自体TIL（肿瘤浸润淋巴细胞）对匹配肿瘤细胞的应答。因此，TME中持续的eATP-P2RY2信号驱动PGE2介导的免疫抑制回路，该回路在基线时已存在，并在免疫治疗期间进一步增强，从而推动适应性耐药。
Extracellular ATP (eATP) accumulates in the tumor microenvironment (TME), where its metabolite adenosine is implicated in promoting immunosuppressive pathways. We found that immunotherapy further increased eATP concentrations in the TME. eATP directly signaled through the purinergic receptor P2RY2 in tumor cells to suppress T cell function, independently of its metabolites. Mechanistically, eATP-P2RY2 signaling drove expression of cyclooxygenase (COX)-1 and COX-2 and downstream accumulation of prostaglandin E2 (PGE ). Genetic deletion or pharmacologic inhibition of P2RY2 reduced baseline intratumoral PGE and prevented therapy-induced PGE accumulation, changed the TME immune infiltrate, restored antitumor T cell responses, and overcame resistance to immune checkpoint blockade, CAR-T, and TCR-T therapies. A P2RY2 antagonist monoclonal antibody recapitulated the in vivo therapeutic benefit and enhanced human autologous tumor-infiltrating lymphocyte responses against matched tumor cells ex vivo. Thus, persistent eATP-P2RY2 signaling in the TME drives a PGE -mediated immunosuppressive circuit that operates at baseline and is further amplified during immunotherapy, driving adaptive resistance.
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