Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function.
Ectonucleotidase CD39 is highly expressed on ATLL cells and is responsible for their immunosuppressive function.
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DOI：
10.1038/s41375-020-0788-y
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发表时间：
2021-01
期刊：
影响因子：
11.4
通讯作者：
Kanakura Y
中科院分区：
文献类型：
--
作者：
Nagate Y;Ezoe S;Fujita J;Okuzaki D;Motooka D;Ishibashi T;Ichii M;Tanimura A;Kurashige M;Morii E;Fukushima T;Suehiro Y;Yokota T;Shibayama H;Oritani K;Kanakura Y
成人T细胞白血病/淋巴瘤（ATLL）患者的预后极差，部分原因是他们的免疫抑制状态。大多数ATLL患者的白血病细胞具有与THL相似的表型，提示ATLL细胞本身具有免疫抑制功能。在这项研究中，我们检测到ATLL细胞上的CD 39表达，特别是在侵袭性亚型上。CD 39和CD 73将细胞外三磷酸腺苷（ATP）转化为腺苷，腺苷是TMF免疫抑制的关键因素。在体外培养中，CD 39 + ATLL细胞和正常T细胞都能迅速将细胞外ATP转化为AMP，这一过程被CD 39抑制剂干扰，并且在CD 39敲除MJ细胞系中被否定。CD 39 + MJ细胞对共培养的CD 4 +/CD 8+正常T细胞的增殖有抑制作用，而CD 39敲除MJ细胞对共培养的CD 4 +/CD 8+正常T细胞的增殖无抑制作用。补充的ATP被具有稳定的CD 39诱导的EG 7-OVA T细胞系耗尽，但未被模拟耗尽。当这些细胞系皮下移植到小鼠胁腹时，Poly（I：C）腹膜给药在模拟移植肿瘤中将肿瘤大小减小至1/3，但在CD 39诱导的肿瘤中没有。总之，我们发现ATLL细胞以高速率表达CD 39，我们的结果表明这有助于ATLL细胞通过细胞外ATP酶-腺苷级联反应逃避抗肿瘤免疫。这些发现将指导未来ATLL治疗的临床策略。
Adult T-cell leukemia/lymphoma (ATLL) patients have an extremely poor prognosis, partly due to their immunosuppressive state. The majority of ATLL patients have leukemic cells with phenotype similar to Tregs, prompting suggestions that ATLL cells themselves have immunosuppressive functions. In this study, we detected CD39 expression on ATLL cells, particularly frequent on aggressive subtypes. CD39 and CD73 convert extracellular adenosine triphosphate (ATP) into adenosine, a key player in Tregs’ immunosuppression. In vitro culture, both CD39+ ATLL cells and normal Tregs converted rapidly extracellular ATP to AMP, which was disturbed by CD39 inhibitors, and was negated in the CD39 knockout MJ cell line. The proliferation of cocultured CD4+/CD8+ normal T cells was suppressed by CD39+ MJ cells, but not by CD39 knockout MJ cells. Supplemented ATP was exhausted by an EG7-OVA T-cell line with stable CD39 induction, but not by mock. When these cell lines were subcutaneously transplanted into murine flanks, Poly(I:C) peritoneal administration reduced tumor size to 1/3 in mock-transplanted tumors, but not in CD39 induced tumors. Overall, we found that ATLL cells express CD39 at a high rate, and our results suggest that this helps ATLL cells escape antitumor immunity through the extracellular ATPDase-Adenosine cascade. These findings will guide future clinical strategies for ATLL treatment.
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