Research Center of Oncology, Ono Pharmaceutical Co., Ltd., Osaka, 618-8585, Japan; Laboratory of Biochemistry, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, 060-0812, Japan.
Department of Pharmacovigilance, Ono Pharmaceutical Co., Ltd., Osaka, 618-8585, Japan.
Biochem Biophys Res Commun. 2021 Jun 30;560:1-6. doi: 10.1016/j.bbrc.2021.04.126. Epub 2021 May 6.
Cancer immunotherapy, especially treatment with monoclonal antibodies (mAbs) that block programmed cell death-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) signaling, has attracted attention as a new therapeutic option for cancer. However, only a limited number of patients have responded to this treatment approach. In this study, we searched for compounds that enhance the efficacy of anti-PD-1 mAb using mixed lymphocyte reaction (MLR), which is a mixed culture system of the two key cells (dendritic and T cells) involved in tumor immunity. We found that amlexanox enhanced production of interferon (IFN)-γ, an indicator of T cell activation, by anti-PD-1 mAb. Amlexanox also induced PD-L1 expression in dendritic cells in MLR, whereas it did not stimulate interleukin-2 production by Jurkat T cells. These results suggest that amlexanox acts on dendritic cells, not T cells, in MLR. Furthermore, it enhanced the antitumor effect of the anti-PD-1 mAb in vivo in a mouse tumor-bearing model. The combination of amlexanox and anti-PD-1 mAb increased the expression of Ifng encoding IFN-γ, IFN-γ-related genes, Cd274 encoding PD-L1, and cytotoxic T cell-related genes in tumors. In conclusion, amlexanox stimulates the antitumor effect of anti-PD-1 mAb by acting on dendritic cells, which in turn activates cytotoxic T cells in tumors.
癌症免疫疗法，特别是使用单克隆抗体（mAb）阻断程序性细胞死亡-1（PD-1）/程序性细胞死亡配体 1（PD-L1）信号通路的治疗方法，作为癌症的一种新的治疗选择引起了关注。然而，只有有限数量的患者对这种治疗方法有反应。在这项研究中，我们使用混合淋巴细胞反应（MLR）搜索了增强抗 PD-1 mAb 疗效的化合物，MLR 是肿瘤免疫中两种关键细胞（树突状细胞和 T 细胞）的混合培养系统。我们发现氨来占诺增强了抗 PD-1 mAb 产生干扰素（IFN）-γ，这是 T 细胞活化的指标。氨来占诺还在 MLR 中诱导树突状细胞表达 PD-L1，而它不会刺激 Jurkat T 细胞产生白细胞介素 2。这些结果表明，氨来占诺在 MLR 中作用于树突状细胞，而不是 T 细胞。此外，它在荷瘤小鼠模型中增强了抗 PD-1 mAb 的抗肿瘤作用。氨来占诺与抗 PD-1 mAb 的联合使用增加了肿瘤中编码 IFN-γ 的 Ifng、IFN-γ 相关基因、编码 PD-L1 的 Cd274 和细胞毒性 T 细胞相关基因的表达。总之，氨来占诺通过作用于树突状细胞刺激抗 PD-1 mAb 的抗肿瘤作用，进而激活肿瘤中的细胞毒性 T 细胞。
