Immunosuppressive cells accumulating in the tumor microenvironment constitute a formidable barrier that interferes with current immunotherapeutic approaches. A unifying feature of these tumor-associated immune and vascular endothelial cells appears to be the elevated expression of ectonucleotidase CD39, which in tandem with ecto-5′-nucleotidase CD73, catalyzes the conversion of extracellular ATP into adenosine. We glycoengineered an afucosylated anti-CD39 IgG2c and tested this reagent in mouse melanoma and colorectal tumor models. We identified major biological effects of this approach on cancer growth, associated with depletion of immunosuppressive cells, mediated through enhanced Fcγ receptor–directed (FcγR-directed), antibody-dependent cellular cytotoxicity (ADCC). Furthermore, regulatory/exhausted T cells lost CD39 expression, as a consequence of antibody-mediated trogocytosis. Most strikingly, tumor-associated macrophages and endothelial cells with high CD39 expression were effectively depleted following antibody treatment, thereby blocking angiogenesis. Tumor site–specific cellular modulation and lack of angiogenesis synergized with chemotherapy and anti–PD-L1 immunotherapy in experimental tumor models. We conclude that depleting suppressive cells and targeting tumor vasculature, through administration of afucosylated anti-CD39 antibody and the activation of ADCC, comprises an improved, purinergic system–modulating strategy for cancer therapy.

中文翻译：

---

糖工程抗 CD39 通过消耗抑制细胞和抑制肿瘤模型中的血管生成来促进抗癌反应

在肿瘤微环境中积累的免疫抑制细胞构成了一个强大的屏障，干扰了当前的免疫治疗方法。这些肿瘤相关免疫和血管内皮细胞的一个共同特征似乎是外核苷酸酶 CD39 的表达升高，它与外 5'-核苷酸酶 CD73 一起催化细胞外 ATP 转化为腺苷。我们对非岩藻糖基化抗 CD39 IgG2c 进行了糖化工程，并在小鼠黑色素瘤和结肠直肠肿瘤模型中测试了该试剂。我们确定了这种方法对癌症生长的主要生物学效应，与免疫抑制细胞的消耗有关，通过增强的 Fcγ 受体导向（FcγR 导向）、抗体依赖性细胞毒性（ADCC）介导。此外，调节/耗尽的 T 细胞失去 CD39 表达，作为抗体介导的吞噬作用的结果。最引人注目的是，具有高 CD39 表达的肿瘤相关巨噬细胞和内皮细胞在抗体治疗后被有效消耗，从而阻断血管生成。在实验性肿瘤模型中，肿瘤部位特异性细胞调节和血管生成缺乏与化学疗法和抗 PD-L1 免疫疗法协同作用。我们得出结论，通过施用非岩藻糖基化抗 CD39 抗体和激活 ADCC 来消耗抑制细胞和靶向肿瘤脉管系统，构成了一种用于癌症治疗的改进的嘌呤能系统调节策略。在实验性肿瘤模型中，肿瘤部位特异性细胞调节和血管生成缺乏与化学疗法和抗 PD-L1 免疫疗法协同作用。我们得出结论，通过施用非岩藻糖基化抗 CD39 抗体和激活 ADCC 来消耗抑制细胞和靶向肿瘤脉管系统，构成了一种用于癌症治疗的改进的嘌呤能系统调节策略。在实验性肿瘤模型中，肿瘤部位特异性细胞调节和血管生成缺乏与化学疗法和抗 PD-L1 免疫疗法协同作用。我们得出结论，通过施用非岩藻糖基化抗 CD39 抗体和激活 ADCC 来消耗抑制细胞和靶向肿瘤脉管系统，构成了一种用于癌症治疗的改进的嘌呤能系统调节策略。