Increased ectonucleotidase expression and activity in regulatory T cells of patients with head and neck cancer.
Increased ectonucleotidase expression and activity in regulatory T cells of patients with head and neck cancer.
复制标题
头颈癌患者调节性 T 细胞中的核酸外切酶表达和活性增加。
DOI：
10.1158/1078-0432.ccr-09-1143
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发表时间：
2009-10-15
影响因子：
11.5
通讯作者：
Whiteside, Theresa L.
中科院分区：
文献类型：
--
作者：
Mandapathil, Magis;Szczepanski, Miroslaw J.;Szajnik, Marta;Ren, Jin;Lenzner, Diana E.;Jackson, Edwin K.;Gorelik, Elieser;Lang, Stephan;Johnson, Jonas T.;Whiteside, Theresa L.
调节性T细胞（Treg）的频率/活性在癌症患者中增加，并在肿瘤逃逸中起主要作用。虽然Treg的存在有利于疾病进展，但Treg用于抑制抗肿瘤免疫的机制尚不清楚。外核苷酸酶CD 39和CD 73在Treg中表达，并将ATP转化为免疫抑制性腺苷。在这项研究中，参与的腺苷能途径Treg介导的抑制HNSCC患者进行了评估。研究了患有活动性疾病（AD）的HNSCC患者（n=19）和治疗后无明显疾病（NED）的患者（n=14）。通过流式细胞术评估CD 4 + T细胞和CD 4 + CD 25 high Treg上的外核苷酸酶表达，并与正常对照（NC）进行比较。还比较了这3组内的外核苷酸酶活性。分析外核苷酸酶表达/功能与疾病分期的相关性。CD 4 + T细胞和Treg中CD 39和CD 73的百分比和表达水平在HNSCC中高于NC，并且在NED中最高。患者的Treg以更高的速率水解ATP并产生比NC的Treg更高水平的腺苷。CD 4 + CD 39+细胞的频率和酶活性增加对应于腺苷介导的效应T细胞抑制的增加，其部分被外核苷酸酶抑制剂ARL 67156和选择性A2 a/A2 b受体拮抗剂ZM 241385抑制。在HNSCC患者中，CD 39 + Treg频率和腺苷介导的抑制显著增加。腺苷能途径参与Treg介导的癌症免疫抑制，其减弱可能是HNSCC患者有希望的免疫策略。
Regulatory T cells (Treg) frequency/activity are increased in cancer patients and play a major in tumor escape. While disease progression is favored by the presence of Treg, mechanisms used by Treg to suppress anti-tumor immunity are unknown. The ectonucleotidases CD39 and CD73 are expressed in Treg and convert ATP into immunosuppressive adenosine. In this study, the involvement of the adenosinergic pathway in Treg-mediated suppression in HNSCC patients was evaluated. HNSCC patients with an active disease (AD) (n=19) and patients with no evident disease (NED) after therapy (n=14) were studied. Ectonucleotidase expression on CD4+ T cells and CD4+CD25high Treg was evaluated by flow cytometry and compared to normal controls (NC). Ectonucleotidase activity was also compared within these 3 groups. The data were analyzed for associations of ectonucleotidase expression/function with disease stage. The percentages and expression levels of CD39 and CD73 in CD4+ T cells and Treg were greater in HNSCC than NC and were highest in NED. Patients' Treg hydrolyzed ATP at higher rates and produced higher levels of adenosine than NC' Treg. The increased frequency and enzymatic activity of CD4+CD39+ cells corresponded to increased adenosine-mediated suppression of effector T cells, which was partly inhibited by ARL67156, an ectonucleotidase inhibitor, and by ZM241385, a selective A2a/A2b receptor antagonist. CD39+ Treg frequency and adenosine-mediated suppression are significantly increased in HNSCC patients. The adenosinergic pathway is involved in Treg-mediated immunosuppression in cancer and its attenuation could be a promising immunotherapeutic strategy for patients with HNSCC.