Natural killer (NK) cell protection from tumor metastases is a critical feature of the host immune response to cancer, but various immunosuppression mechanisms limit NK cell effector function. The ectoenzyme, CD39, expressed on tumor-infiltrating myeloid cells, granulocytes, and lymphocytes, including NK cells, converts extracellular ATP (eATP) into AMP and, thus, potentially suppresses eATP-mediated proinflammatory responses. A CD39-targeting monoclonal antibody (mAb) that inhibits the mouse ectoenzyme CD39 suppressed experimental and spontaneous metastases in a number of different tumor models and displayed superior antimetastatic activity compared with the CD39 inhibitor POM1 and inhibitors and mAbs that block other members of the adenosinergic family (e.g., A2AR and CD73). The antimetastatic activity of anti-CD39 was NK cell and IFNγ dependent, and anti-CD39 enhanced the percentage and quantity of IFNγ produced and CD107a expression in lung-infiltrating NK cells following tumor challenge and anti-CD39 therapy. Using conditional Cd39 gene-targeted mouse strains and adoptive NK cell transfers, we showed that CD39 expressed on bone marrow-derived myeloid cells was essential for anti-CD39's antimetastatic activity, but NK cell expression of CD39 was not critical. The eATP receptor P2X7 and the NALP3 inflammasome, including downstream IL18, were critical in the mechanism of action of anti-CD39, and the frequency of P2X7 and CD39 coexpressing lung alveolar macrophages was specifically reduced 1 day after anti-CD39 therapy. The data provide a mechanism of action involving NK cells and myeloid cells, and anti-CD39 combined with anti-PD-1, NK cell-activating cytokines IL15 or IL2, or an inhibitor of A2AR to effectively suppress tumor metastases.

中文翻译：

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通过骨髓 CD39 和 NK 细胞效应器功能控制转移。

自然杀伤 (NK) 细胞免受肿瘤转移是宿主对癌症免疫反应的一个关键特征，但各种免疫抑制机制限制了 NK 细胞的效应功能。胞外酶 CD39 在肿瘤浸润性骨髓细胞、粒细胞和淋巴细胞（包括 NK 细胞）上表达，将细胞外 ATP (eATP) 转化为 AMP，因此可能抑制 eATP 介导的促炎反应。一种抑制小鼠胞外酶 CD39 的 CD39 靶向单克隆抗体 (mAb) 在许多不同的肿瘤模型中抑制了实验性和自发性转移，与 CD39 抑制剂 POM1 以及阻断腺苷能家族其他成员的抑制剂和 mAb 相比，显示出优异的抗转移活性（例如，A2AR 和 CD73）。抗 CD39 的抗转移活性依赖于 NK 细胞和 IFNγ，在肿瘤攻击和抗 CD39 治疗后，抗 CD39 增强了肺浸润性 NK 细胞中产生的 IFNγ 的百分比和数量以及 CD107a 的表达。使用有条件的 Cd39 基因靶向小鼠品系和过继 NK 细胞转移，我们表明在骨髓来源的骨髓细胞上表达的 CD39 对于抗 CD39 的抗转移活性是必不可少的，但 CD39 的 NK 细胞表达并不重要。eATP 受体 P2X7 和 NALP3 炎性体，包括下游 IL18，在抗 CD39 的作用机制中至关重要，并且在抗 CD39 治疗后 1 天，P2X7 和 CD39 共表达肺泡巨噬细胞的频率特别降低。数据提供了涉及 NK 细胞和骨髓细胞、抗 CD39 联合抗 PD-1、NK 细胞激活细胞因子 IL15 或 IL2 的作用机制，