CD39 Expression Defines Cell Exhaustion in Tumor-Infiltrating CD8+ T Cells
CD39 Expression Defines Cell Exhaustion in Tumor-Infiltrating CD8+ T Cells
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DOI：
10.1158/0008-5472.can-16-2684
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发表时间：
2018-01-01
期刊：
影响因子：
11.2
通讯作者：
Montes, Carolina L.
中科院分区：
文献类型：
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作者：
Canale, Fernando P.;Ramello, Maria C.;Montes, Carolina L.
CD8(+) T 淋巴细胞消除肿瘤的能力受到其产生免疫抑制微环境的能力的限制。在这里，我们描述了肿瘤浸润性 CD8(+) T 细胞的一个子集，其特征是免疫抑制性 ATP 核酸外切酶 CD39 的高表达。 CD39（高）CD8（+）T细胞的频率随着肿瘤的生长而增加，但在淋巴器官中不存在。高表达CD39的肿瘤浸润CD8+T细胞表现出耗竭特征，例如TNF和IL2的产生减少以及共抑制受体的表达减少。小鼠耗尽的 CD39(+)CD8(+) T 细胞水解细胞外 ATP，证实 CD39 具有酶活性。此外，耗尽的CD39(+)CD8(+) T细胞抑制应答CD8(+) T细胞产生IFN-γ。在乳腺癌和黑色素瘤患者的标本中，CD39(+)CD8(+) T细胞存在于肿瘤和受侵袭或转移的淋巴结中，但在非受侵袭的淋巴结中几乎检测不到，并且在外周血中不存在。这些细胞表现出疲惫的表型，IFNγ、TNF、IL2 的产生受损，并且共抑制受体的高表达。尽管T细胞受体的结合足以诱导人CD8(+) T细胞上的CD39，但暴露于IL6和IL27会促进来自人或鼠源的刺激的CD8(+) T细胞上的CD39表达。我们的研究结果表明，肿瘤微环境如何驱动 CD39 作为 CD8+ T 细胞上的免疫调节分子，这对定义 T 细胞功能障碍的生物标志物和免疫治疗干预的靶点具有重要意义。 (C) 2017 年 AACR。
The ability of CD8(+) T lymphocytes to eliminate tumors is limited by their ability to engender an immunosuppressive microenvironment. Here we describe a subset of tumor-infiltrating CD8(+) T cells marked by high expression of the immunosuppressive ATP ectonucleotidase CD39. The frequency of CD39(high)CD8(+) T cells increased with tumor growth but was absent in lymphoid organs. Tumor-infiltrating CD8(+) T cells with high CD39 expression exhibited features of exhaustion, such as reduced production of TNF and IL2 and expression of coinhibitory receptors. Exhausted CD39(+)CD8(+) T cells from mice hydrolyzed extracellular ATP, confirming that CD39 is enzymatically active. Furthermore, exhausted CD39(+)CD8(+) T cells inhibited IFN gamma production by responder CD8(+) T cells. In specimens from breast cancer and melanoma patients, CD39(+)CD8(+) T cells were present within tumors and invaded or metastatic lymph nodes, but were barely detectable within non-invaded lymph nodes and absent in peripheral blood. These cells exhibited an exhausted phenotype with impaired production of IFN gamma, TNF, IL2, and high expression of coinhibitory receptors. Although T-cell receptor engagement was sufficient to induce CD39 on human CD8(+) T cells, exposure to IL6 and IL27 promoted CD39 expression on stimulated CD8(+) T cells from human or murine sources. Our findings show how the tumor microenvironment drives the acquisition of CD39 as an immune regulatory molecule on CD8(+) T cells, withimplications for defining abiomarker of T-cell dysfunction and a target for immunotherapeutic intervention. (C) 2017 AACR.