Institute of Chinese Medical Sciences, State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macau, China.
Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
J Immunother Cancer. 2022 Nov;10(11). doi: 10.1136/jitc-2022-005241.
Tumor necrosis factor receptor type 2 (TNFR2) is primarily expressed by CD4FoxP3 regulatory T cells (Tregs), especially those present in tumor microenvironment. There is compelling evidence that TNFR2 plays a crucial role in the activation, expansion, and phenotypic stability of Tregs and promotes tumor immune evasion. Understanding of epigenetic regulation of TNFR2 expression in Tregs may help device a novel strategy in cancer immunotherapy.
MiR-125b-5p-overexpressing or knockdown murine CD4 T cells and Tregs were constructed, and the effect of miR-125b-5p on Tregs proliferation, suppressive function and TNFR2 expression were examined. In vivo antitumor efficacy of Ago-125b-5p (miR-125b-5p agomir) was evaluated in MC38 tumor bearing mice, and tumor-infiltrating Tregs and CD8 cytotoxic T lymphocytes (CTLs) were analyzed. RNA-seq analysis was applied to reveal the genes and signaling pathways regulated by miR-125b-5p in Tregs.
In this study, we found that TNFR2 was a direct target of miR-125b-5p. Overexpression of miR-125b-5p decreased the proportion of Tregs and their expression of TNFR2 and consequently inhibited its proliferation and suppressive function by regulating the metabolism-related signaling pathways. Moreover, in colon cancer bearing mice, the administration of Ago-125b-5p markedly inhibited the tumor growth, which was associated with reduction of Tregs and increase of IFNγCD8 T cells in tumor environment. Furthermore, in human colon adenocarcinoma patients, we verified that miR-125b-5p expression was downregulated, and low levels of miR-125b-5p were associated with poor prognosis. Interestingly, the expression of miR-125b-5p and TNFR2 were negatively correlated.
Our study for the first time found that the expression of TNFR2 by Tregs was regulated by miR-125b-5p. Our results showed that miR-125b-5p had the capacity to inhibit the expression of TNFR2 and immunosuppressive activity of Tregs and consequently enhanced the antitumor efficacy. This property of miR-125b-5p may be therapeutically harnessed in the treatment of human cancers.
肿瘤坏死因子受体 2（TNFR2）主要由 CD4FoxP3 调节性 T 细胞（Tregs）表达，尤其是存在于肿瘤微环境中的 Tregs。有强有力的证据表明，TNFR2 在 Tregs 的激活、扩增和表型稳定性中发挥着关键作用，并促进肿瘤的免疫逃逸。了解 Tregs 中 TNFR2 表达的表观遗传调控可能有助于设计癌症免疫治疗的新策略。
构建了 miR-125b-5p 过表达或敲低的小鼠 CD4 T 细胞和 Tregs，研究了 miR-125b-5p 对 Tregs 增殖、抑制功能和 TNFR2 表达的影响。在 MC38 荷瘤小鼠中评估了 Ago-125b-5p（miR-125b-5p 激动剂）的抗肿瘤疗效，并分析了肿瘤浸润性 Tregs 和 CD8 细胞毒性 T 淋巴细胞（CTLs）。应用 RNA-seq 分析揭示了 miR-125b-5p 在 Tregs 中调控的基因和信号通路。
本研究发现 TNFR2 是 miR-125b-5p 的直接靶标。miR-125b-5p 的过表达降低了 Tregs 的比例及其 TNFR2 的表达，进而通过调节代谢相关信号通路抑制其增殖和抑制功能。此外，在结肠癌荷瘤小鼠中，Ago-125b-5p 的给药显著抑制了肿瘤生长，这与肿瘤微环境中 Tregs 的减少和 IFNγCD8 T 细胞的增加有关。此外，在人类结肠癌患者中，我们验证了 miR-125b-5p 的表达下调，并且低水平的 miR-125b-5p 与预后不良相关。有趣的是，miR-125b-5p 和 TNFR2 的表达呈负相关。
本研究首次发现 Tregs 中 TNFR2 的表达受 miR-125b-5p 调节。我们的研究结果表明，miR-125b-5p 具有抑制 TNFR2 表达和 Tregs 免疫抑制活性的能力，从而增强了抗肿瘤疗效。miR-125b-5p 的这种特性可能在人类癌症的治疗中得到治疗利用。
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