Glycoengineered anti-CD39 promotes anticancer responses by depleting suppressive cells and inhibiting angiogenesis in tumor models.
Glycoengineered anti-CD39 promotes anticancer responses by depleting suppressive cells and inhibiting angiogenesis in tumor models.
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糖基化抗CD39通过消耗肿瘤模型中的抑制性细胞和抑制血管生成来促进抗癌反应。
DOI：
10.1172/jci157431
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发表时间：
2022-07-01
影响因子：
15.9
通讯作者：
Robson, Simon C.
中科院分区：
文献类型：
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作者：
Zhang, Haohai;Feng, Lili;Mello, Paola de Andrade;Mao, Changchuin;Near, Richard;Csizmadia, Eva;Chan, Leo Li-Ying;Enjyoji, Keiichi;Gao, Wenda;Zhao, Haitao;Robson, Simon C.
在肿瘤微环境中积累的免疫抑制细胞构成了干扰当前免疫治疗方法的强大屏障。这些肿瘤相关免疫细胞和血管内皮细胞的一个统一特征似乎是外核苷酸酶CD 39的表达升高，它与外5 '-核苷酸酶CD 73协同催化细胞外ATP转化为腺苷。我们对无岩藻糖基化抗CD39 IgG2c进行了糖工程改造，并在小鼠黑色素瘤和结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，与免疫抑制细胞的耗竭相关，通过增强Fc γ受体导向（Fc γ R导向）、抗体依赖性细胞毒性（ADCC）介导。此外，调节/耗尽的T细胞失去了CD39表达，作为抗体介导的胞刺的结果。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处理后被有效地耗尽，从而阻断血管生成。肿瘤位点特异性细胞调节和缺乏血管生成与化疗和抗PD-L1免疫治疗在实验肿瘤模型中协同作用。我们的结论是，通过给予无岩藻糖基化抗CD39抗体和激活ADCC，消除抑制细胞和靶向肿瘤血管系统，包括一种改进的嘌呤能系统调节策略，用于癌症治疗。
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.
影响因子：
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作者：
Mao C;Near R;Zhong X;Gao W
通讯作者：
Gao W
影响因子：
7.3
作者：
Vaupel P;Multhoff G
通讯作者：
Multhoff G