College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.
Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, Jiangsu, China; Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, Soochow University, Suzhou, Jiangsu, China.
Cancer Lett. 2020 Aug 10;485:14-26. doi: 10.1016/j.canlet.2020.04.013. Epub 2020 May 14.
The Insulin-like growth factor-1/Insulin-like growth factor-1 receptor (IGF1/IGF1R) axis contributes to immunosuppression during tumor progression; however, the underlying mechanism remains unclear. In the present study, we found that IGF1 stimulation or IGF1R overexpression (IGF1R-OE) could upregulate the expression of B7-H4, while IGF1R inhibition downregulated B7-H4 in both A549 and SPC-A-1 lung cancer cell lines. IGF1R-OE conferred the inhibition of CD8 T cells by cancer cells in vitro, and induction of B7-H4 expression was mediated by the activation of the MEK/ERK1/2 signaling pathway. The in vitro findings were further confirmed in vivo using a Lewis lung cancer mouse model. IGF1R-OE promoted tumor growth and inhibited tumor infiltration by CD8 T cells in the mouse model. However, this effect was suppressed when B7-H4 was knocked down in IGF1R-OE cells. Our findings suggest that IGF1R could induce immunosuppression in lung cancer by upregulating the expression of B7-H4 through the MEK/ERK pathway. B7-H4 may therefore be a potential therapeutic target for lung cancer immunotherapy.
胰岛素样生长因子-1/胰岛素样生长因子-1 受体 (IGF1/IGF1R) 轴在肿瘤进展过程中有助于免疫抑制；然而，其潜在机制尚不清楚。在本研究中，我们发现 IGF1 刺激或 IGF1R 过表达 (IGF1R-OE) 可上调 B7-H4 的表达，而 IGF1R 抑制在 A549 和 SPC-A-1 肺癌细胞系中均可下调 B7-H4 的表达。IGF1R-OE 赋予癌细胞在体外抑制 CD8 T 细胞的能力，而 B7-H4 表达的诱导是通过 MEK/ERK1/2 信号通路的激活介导的。使用 Lewis 肺癌小鼠模型进一步证实了体外研究结果。IGF1R-OE 促进了小鼠模型中肿瘤的生长，并抑制了 CD8 T 细胞浸润肿瘤。然而，当 IGF1R-OE 细胞中的 B7-H4 被敲低时，这种作用被抑制。我们的研究结果表明，IGF1R 可通过 MEK/ERK 通路上调 B7-H4 的表达诱导肺癌中的免疫抑制。B7-H4 因此可能是肺癌免疫治疗的一个潜在治疗靶点。
