Department of Gastrointestinal Surgery, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
The Affiliated Drum Tower Clinical College of Nanjing Medical University, Nanjing, China.
Biomed Res Int. 2019 Dec 14;2019:4093214. doi: 10.1155/2019/4093214. eCollection 2019.
BACKGROUND: Adenosine, derived from the degradation of ATP via ectonucleotidases CD39 and CD73, is a critical immunosuppressive metabolite in the hypoxic microenvironment of tumor tissue. Adenosine signaling via A2aR can inhibit the antitumor immune response of CD8 T cells. CD39 and CD73 high-expressing Tregs play a critical role in tumor immune evasion of gastric cancer (GC). The present study investigated the underlying mechanism by which Tregs suppress antitumor immune responses in GC. MATERIALS AND METHODS: Fifty-two GC samples were collected, and the frequency of FoxP3 Tregs and CD8 T cells and density ratios of A2aR/CD8 T cells, CD39/FoxP3 Tregs, and CD73/FoxP3 Tregs in GC were assessed with multiplex immunofluorescence. The expression of FoxP3 and A2aR in GC tissues was also detected by the immunoblotting assay. We next investigated the relationship between density of FoxP3 Tregs, ratio of A2aR/CD8 T cells, and clinicopathological parameters. At the same time, Tregs and CD8 T cells were isolated from peripheral blood of five GC patients, and the antagonists of CD39 and CD73 were used to assess the ability of Tregs to decompose ATP into adenosine. In addition, we cocultured CD8 T cells and Tregs with antagonists of AR and AR in order to examine the alterations in immune function of CD8 T cells. RESULTS: The density of both FoxP3 Tregs and A2aR/CD8 T cells was higher in GC tissue compared to peritumoral normal tissue and significantly correlated with the TNM stage, lymph node metastasis, and distant metastasis of GC. The process of Treg hydrolysis of ATP into adenosine was blocked by the antagonists of CD39 and CD73. In addition, Tregs could induce apoptosis and inhibit proliferation of CD8 T cells, while this effect could be obviously reduced by applying the antagonist of AR or ARAR. Moreover, IFN-, TNF-, and perforin generated by CD8 T cells could also be inhibited through the adenosine A2aR pathway. CONCLUSIONS: The FoxP3 Tregs and A2aR/CD8 T cells were excessively infiltrated in GC tissue. Tregs from GC can decompose ATP to adenosine and in turn induce apoptosis and inhibit the proliferation of CD8 T cells through the A2aR pathway, further leading to immune escape of GC.
背景：腺苷是由细胞外核苷酸酶 CD39 和 CD73 降解 ATP 产生的，是肿瘤组织低氧微环境中一种关键的免疫抑制代谢物。通过 A2aR 信号传导的腺苷可以抑制 CD8 T 细胞的抗肿瘤免疫反应。CD39 和 CD73 高表达的 Tregs 在胃癌（GC）的肿瘤免疫逃逸中起着关键作用。本研究探讨了 Tregs 抑制 GC 中抗肿瘤免疫反应的潜在机制。
材料和方法：收集了 52 例 GC 样本，通过多重免疫荧光法评估了 FoxP3 Tregs 和 CD8 T 细胞的频率以及 A2aR/CD8 T 细胞、CD39/FoxP3 Tregs 和 CD73/FoxP3 Tregs 的密度比。还通过免疫印迹法检测了 GC 组织中 FoxP3 和 A2aR 的表达。接下来，我们研究了 FoxP3 Tregs 的密度、A2aR/CD8 T 细胞的比值与临床病理参数之间的关系。同时，从 5 例 GC 患者的外周血中分离 Tregs 和 CD8 T 细胞，并使用 CD39 和 CD73 的拮抗剂来评估 Tregs 将 ATP 分解为腺苷的能力。此外，我们将 CD8 T 细胞和 Tregs 与 AR 和 AR 的拮抗剂共培养，以检查 CD8 T 细胞免疫功能的变化。
结果：与肿瘤周围正常组织相比，GC 组织中 FoxP3 Tregs 和 A2aR/CD8 T 细胞的密度更高，且与 GC 的 TNM 分期、淋巴结转移和远处转移显著相关。CD39 和 CD73 的拮抗剂阻断了 Treg 将 ATP 水解为腺苷的过程。此外，Tregs 可诱导 CD8 T 细胞凋亡并抑制其增殖，而通过应用 AR 或 ARAR 的拮抗剂可明显降低这种作用。此外，CD8 T 细胞产生的 IFN-γ、TNF-α和穿孔素也可通过腺苷 A2aR 途径受到抑制。
结论：FoxP3 Tregs 和 A2aR/CD8 T 细胞在 GC 组织中过度浸润。GC 中的 Tregs 可以将 ATP 分解为腺苷，并通过 A2aR 途径诱导 CD8 T 细胞凋亡和抑制其增殖，进而导致 GC 的免疫逃逸。
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