Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan.
Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo 157-8777, Japan.
Int Immunol. 2022 Dec 31;34(12):609-619. doi: 10.1093/intimm/dxac035.
Antibodies that block the interaction between PD-1 and PD-1 ligands (anti-PD-1) are in clinical use for the treatment of cancer, yet their efficacy is limited. Pre-approved therapies that enhance the effect of anti-PD-1 in combination are beneficial. Small-molecule inhibitors that attenuate T cell receptor signaling are reported to prevent T cell exhaustion and induce memory T cells with stem cell potential, resulting in a durable effector T cell response in combination with anti-PD-1. In search of such targets, we focused on protein kinase D (PKD), which is suggested to be suppressive in both tumor growth and TCR signaling. We report that CRT0066101, a PKD inhibitor (PKDi), suppressed the growth of mouse tumors at a sub-micromolar concentration in vitro. Despite its inhibitory effects on tumors, a single treatment of tumor-bearing mice with PKDi did not inhibit, but rather accelerated tumor growth, and reversed the therapeutic effect of anti-PD-1. Mice treated with PKDi showed reduced T cell infiltration and defects in the generation of effector T cells, compared to those treated with anti-PD-1, suggesting that PKDi inhibited ongoing antitumor responses. Mechanistically, PKDi inhibited phosphorylation of AKT, a primary checkpoint that is reactivated by anti-PD-1. In conclusion, PKD is fundamentally required for T cell reactivation by anti-PD-1; therefore, inhibition of PKD is not appropriate for combination therapy with anti-PD-1. On the other hand, a single dose of PKDi was shown to strongly suppress experimental autoimmunity in mice, indicating that PKDi could be useful for the treatment of immune-related adverse events that are frequently reported in anti-PD-1 therapy.
阻断 PD-1 与 PD-1 配体相互作用的抗体（抗 PD-1）已用于癌症的临床治疗，但疗效有限。增强抗 PD-1 联合治疗效果的预批准疗法是有益的。据报道，抑制 T 细胞受体信号的小分子抑制剂可防止 T 细胞衰竭，并诱导具有干细胞潜力的记忆 T 细胞，从而在与抗 PD-1 联合使用时产生持久的效应 T 细胞反应。在寻找此类靶点时，我们专注于蛋白激酶 D（PKD），它被认为在肿瘤生长和 TCR 信号中都具有抑制作用。我们报告称，PKD 抑制剂（PKDi）CRT0066101 在体外以亚微米浓度抑制小鼠肿瘤的生长。尽管 PKDi 对肿瘤具有抑制作用，但单次治疗荷瘤小鼠不仅不能抑制肿瘤生长，反而加速了肿瘤生长，并逆转了抗 PD-1 的治疗效果。与接受抗 PD-1 治疗的小鼠相比，接受 PKDi 治疗的小鼠显示 T 细胞浸润减少，效应 T 细胞生成缺陷，这表明 PKDi 抑制了正在进行的抗肿瘤反应。从机制上讲，PKDi 抑制 AKT 的磷酸化，AKT 是抗 PD-1 重新激活的主要检查点。总之，PKD 是抗 PD-1 激活 T 细胞所必需的；因此，抑制 PKD 不适合与抗 PD-1 联合治疗。另一方面，单次给予 PKDi 可强烈抑制小鼠的实验性自身免疫，表明 PKDi 可用于治疗抗 PD-1 治疗中经常报告的免疫相关不良事件。
