Leeds Institute of Cancer & Pathology Wellcome Trust Brenner Building, St James's University Hospital, Leeds United Kingdom.
Cell Signaling Section, Department of Pathology, Tennis Court Road, University of Cambridge, Cambridge, United Kingdom.
Cancer Res. 2018 Feb 1;78(3):706-717. doi: 10.1158/0008-5472.CAN-17-0491. Epub 2017 Oct 20.
The impact of PD-1 immune checkpoint therapy prompts exploration of other strategies to downregulate PD-1 for cancer therapy. We previously showed that the serine/threonine kinase, glycogen synthase kinase, GSK-3α/β, is a central regulator of PD-1 transcription in CD8 T cells. Here, we show that the use of small-molecule inhibitors of GSK-3α/β (GSK-3i) to reduce (PD-1) transcription and expression was as effective as anti-PD-1 and PD-L1-blocking antibodies in the control of B16 melanoma, or EL4 lymphoma, in primary tumor and metastatic settings. Furthermore, the conditional genetic deletion of GSK-3α/β reduced PD-1 expression on CD8 T cells and limited B16 pulmonary metastasis to the same degree as PD-1 gene deficiency. In each model, GSK-3i inhibited PD-1 expression on tumor-infiltrating lymphocytes, while increasing (T-bet) transcription, and the expression of CD107a (LAMP1) and granzyme B (GZMB) on CD8 T cells. Finally, the adoptive transfer of T cells treated with a GSK-3 inhibitor delayed the onset of EL4 lymphoma growth to a similar extent as anti-PD-1 pretreatment. Overall, our findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8 T-cell function in cancer therapy to a similar degree as PD-1-blocking antibodies. These findings show how GSK-3 inhibitors that downregulate PD-1 expression can enhance CD8 T-cell function in cancer therapy to a similar degree as PD-1 blocking antibodies, offering a next-generation approach in the design of immunotherapeutic approaches for cancer management. .
PD-1 免疫检查点治疗的影响促使人们探索其他下调 PD-1 以用于癌症治疗的策略。我们之前表明，丝氨酸/苏氨酸激酶糖原合酶激酶 GSK-3α/β是 CD8 T 细胞中 PD-1 转录的中央调节剂。在这里，我们表明，使用 GSK-3α/β（GSK-3i）小分子抑制剂来降低（PD-1）转录和表达与抗 PD-1 和 PD-L1 阻断抗体在控制 B16 黑色素瘤或 EL4 淋巴瘤中的效果一样有效原发性肿瘤和转移环境。此外，GSK-3α/β 的条件基因缺失降低了 CD8 T 细胞上的 PD-1 表达，并限制了 B16 肺转移到与 PD-1 基因缺陷相同的程度。在每种模型中，GSK-3i 抑制了肿瘤浸润淋巴细胞上的 PD-1 表达，同时增加了（T-bet）转录以及 CD8 T 细胞上 CD107a（LAMP1）和颗粒酶 B（GZMB）的表达。最后，用 GSK-3 抑制剂处理的 T 细胞的过继转移延迟了 EL4 淋巴瘤生长的发生，其程度与抗 PD-1 预处理相同。总体而言，我们的研究结果表明，下调 PD-1 表达的 GSK-3 抑制剂如何在癌症治疗中增强 CD8 T 细胞功能，其程度与 PD-1 阻断抗体相同。这些发现表明，下调 PD-1 表达的 GSK-3 抑制剂可以增强癌症治疗中的 CD8 T 细胞功能，与 PD-1 阻断抗体的效果相当，为癌症管理的免疫治疗方法的设计提供了一种下一代方法。
