Zheng Yawen, Liu Yanan, Zhang Fang, Su Chen, Chen Xiaozheng, Zhang Mingyan, Sun Meili, Sun Yuping, Xing Ligang
Department of Oncology, Central hospital affiliated to Shandong First Medical University, Jinan, Shandong, P. R. China; Department of Radiation Oncology, Shandong Key Laboratory of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, P. R. China; Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong, P. R. China; Research Center of Translational Medicine, Laboratory Animal Center, Central hospital affiliated to Shandong First Medical University, Jinan, Shandong, P. R. China.
Department of Oncology, Jinan Central Hospital, Shandong University, Jinan, Shandong, P. R. China; Research Center of Translational Medicine, Laboratory Animal Center, Central hospital affiliated to Shandong First Medical University, Jinan, Shandong, P. R. China.
Transl Res. 2023 Feb;252:79-90. doi: 10.1016/j.trsl.2022.08.005. Epub 2022 Aug 7.
KRAS mutation is a common driver in solid tumors, and KRAS-mutated tumors are relatively resistant to radiotherapy. Therefore, we investigated the combined effect of radiation and KRAS-MEK inhibitors (AMG510 and trametinib) in KRAS-mutated tumors. The expression of programmed death-ligand 1 (PD-L1), major histocompatibility complex (MHC) class I molecules, and cytokines in KRAS-mutated cell lines was assessed using flow cytometry, western blot analysis, quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay. In vivo, tumor growth, T cell infiltration, and gene sequencing analyses were conducted in 2 murine KRAS-mutated models. Both AMG510 and trametinib decreased the radiation-induced increase in PD-L1 expression. Radiation and trametinib additively induced the expression of CXCL10 and CXCL11 cytokines and MHC class I in murine CT26 and LLC cell lines. The combination of trametinib and radiation controlled tumor growth and induced more infiltration of CD4 and CD8 T cells in vivo, wherein tumor inhibition function and the survival period of mice could be reduced by CD8 and/or CD4 T cell depletion. The expression levels of immune-related genes also increased in the combination therapy group. Our results indicate that KRAS-MEK inhibitors in combination with radiotherapy can enhance antitumor immunity, providing new therapeutic strategies for KRAS-mutated tumors.
KRAS 突变是实体瘤中常见的驱动因素，KRAS 突变的肿瘤对放疗相对耐药。因此，我们研究了放疗与 KRAS-MEK 抑制剂（AMG510 和曲美替尼）联合应用于 KRAS 突变肿瘤的效果。使用流式细胞术、蛋白质免疫印迹分析、定量聚合酶链反应和酶联免疫吸附测定法评估 KRAS 突变细胞系中程序性死亡配体 1（PD-L1）、主要组织相容性复合体（MHC）I 类分子和细胞因子的表达。在体内，对 2 种小鼠 KRAS 突变模型进行了肿瘤生长、T 细胞浸润和基因测序分析。AMG510 和曲美替尼均降低了放疗诱导的 PD-L1 表达增加。放疗和曲美替尼在小鼠 CT26 和 LLC 细胞系中可累加诱导 CXCL10 和 CXCL11 细胞因子以及 MHC I 类分子的表达。曲美替尼与放疗联合应用可在体内控制肿瘤生长并诱导更多 CD4 和 CD8 T 细胞浸润，其中 CD8 和/或 CD4 T 细胞耗竭可降低肿瘤抑制功能和小鼠生存期。联合治疗组中免疫相关基因的表达水平也有所增加。我们的结果表明，KRAS-MEK 抑制剂与放疗联合应用可增强抗肿瘤免疫力，为 KRAS 突变肿瘤提供了新的治疗策略。
