CD8+CD57+T cells exhibit distinct features in human non-small cell lung cancer
CD8+CD57+T cells exhibit distinct features in human non-small cell lung cancer
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CD8( )CD57( )T 细胞在人非小细胞肺癌中表现出独特的特征
DOI：
10.1136/jitc-2020-000639
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发表时间：
2020-01-01
影响因子：
10.9
通讯作者：
Li, Lequn
中科院分区：
文献类型：
--
作者：
Huang, Bing;Liu, Rong;Li, Lequn
背景慢性感染时反复抗原刺激常导致CD 8（+）CD 57（+）T细胞聚集。这些细胞表达高水平的干扰素-γ、颗粒酶B和穿孔素，具有升高的细胞溶解作用，并且被认为是对抗慢性病毒感染的最有效的细胞。CD 8（+）CD 57（+）T细胞在非小细胞肺癌（NSCLC）中的状态尚未得到很好的定义。方法采用流式细胞术检测NSCLC患者外周血、肿瘤组织及相应正常组织、肺引流淋巴结中CD 8（+）CD 57（+）T细胞的分布、免疫表型及功能特性。结果CD 57（+）T细胞在所有受试隔室中均表达高水平的程序性细胞死亡-1（PD-1），且主要为CD 8（+）T细胞。外周血中的这些细胞表现出终末分化表型，其定义为在表达KLRG 1的同时丧失CD 27和CD 28。CD 8（+）CD 57（+）T细胞表现出增强的细胞毒效力和受损的增殖能力。与外周血中的CD 57（+）T细胞不同，原发性肿瘤中相当大比例的CD 57（+）T细胞表达CD 27和CD 28。肿瘤中的CD 8（+）CD 57（+）T细胞缺乏细胞毒活性。这些细胞的增殖活性也受损。相应正常肺组织中的CD 8（+）CD 57（+）T细胞与其在外周血中的对应物具有相似性，而肿瘤组织中的对应物则不具有相似性。肺引流淋巴结中绝大多数CD 8（+）CD 57（+）T细胞为CD 27和CD 28阳性。这些细胞不能产生穿孔素和颗粒酶B，但它们的增殖活性得以保留。肿瘤中的CD 8（+）CD 57（+）T细胞对PD-1阻断的反应低于其CD 8（+）CD 57（-）对应物。白细胞介素（IL）-15优先恢复这些细胞的效应功能。此外，IL-15能够恢复肿瘤和外周血中CD 8（+）CD 57（+）T细胞受损的增殖活性。结论我们的数据表明，免疫系统抵抗癌症进展的失败可能是由于CD 8（+）T细胞功能成熟受损，在肿瘤微环境中完全分化为效应T细胞。增强IL-15活性可能促进肿瘤反应性CD 8（+）T细胞功能成熟，同时保持其增殖活性。
Background The repetitive antigen stimulation during chronic infection often leads to the accumulation of CD8(+)CD57(+)T cells. These cells express high levels of interferon-gamma, granzyme B and perforin with elevated cytolytic effect, and are considered as the most potent cells for combating chronical viral infection. The status of CD8(+)CD57(+)T cells in non-small cell lung cancer (NSCLC) has not been well defined. Methods We used flow cytometry and undertook a systemic approach to examine the frequency, immunophenotyping and functional properties of CD8(+)CD57(+)T cells in the peripheral blood, tumor tissue and the corresponding normal tissue, as well as lung draining lymph nodes, of patients with NSCLC. Results CD57(+)T cells expressed high levels of programmed cell death-1 (PD-1) in all tested compartments and were predominantly CD8(+)T cells. These cells in the peripheral blood displayed a terminally differentiated phenotype as defined by loss of CD27 and CD28 while expressing KLRG1. CD8(+)CD57(+)T cells exhibited enhanced cytotoxic potencies and impaired proliferative capability. Unlike CD57(+)T cells in the peripheral blood, a significant proportion of CD57(+)T cells in the primary tumors expressed CD27 and CD28. CD8(+)CD57(+)T cells in tumors lacked cytotoxic activity. The proliferative activity of these cells was also impaired. CD8(+)CD57(+)T cells in the corresponding normal lung tissues shared similarities with their counterparts in peripheral blood rather than their counterparts in tumors. The vast majority of CD8(+)CD57(+)T cells in lung draining lymph nodes were positive for CD27 and CD28. These cells were unable to produce perforin and granzyme B, but their proliferative activity was preserved. CD8(+)CD57(+)T cells in tumors displayed an inferior response to PD-1 blockade compared with their CD8(+)CD57(-)counterparts. Interleukin (IL)-15 preferentially restored the effector function of these cells. Additionally, IL-15 was able to restore the impaired proliferative activity of CD8(+)CD57(+)T cells in tumors and peripheral blood. Conclusions Our data indicate that the failure of the immune system to fight cancer progression could be a result of impaired CD8(+)T-cell functional maturation into fully differentiated effector T cells within the tumor microenvironment. Boosting IL-15 activity might promote tumor-reactive CD8(+)T-cell functional maturation while preserving their proliferative activity.