Sun Yiting, Yang Bowen, Wen Ti, Guo Xiaoyu, Li Danni, Shi Ruichuan, Zhang Fuqiang, Wang Dongni, Li Ce, Qu Xiujuan
Department of Medical Oncology, the First Hospital of China Medical University, Shenyang, Liaoning, China.
Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, the First Hospital of China Medical University, Shenyang, Liaoning, China.
Cell Biol Toxicol. 2025 Jan 10;41(1):25. doi: 10.1007/s10565-024-09982-2.
Microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC) patients are the dominant population in immune checkpoint blockade treatments, while more than half of them could not benefit from single-agent immunotherapy. We tried to identify the biomarker of MSI-H CRC and explore its role and mechanism in anti-PD-1 treatments. Tumor-specific MHC-II was linked to a better response to anti-PD-1 in MSI-H CRC and CD74 promoted assembly and transport of HLA-DR dimers.
The characteristic gene was screened by data analysis of single-cell and bulk transcriptome sequencing from public datasets. MSI-H CRC cells co-cultured with peripheral blood mononuclear cells and syngeneic model in C57BL/6 mice were performed to detect the sensitivity to anti-PD-1 treatments respectively.
ANXA10 was identified as a characteristic gene of MSI-H CRC and its expression was obviously greater in MSI-H than MSS CRC. ANXA10 significantly sensitized MSI-H CRC to anti-PD-1 treatments in vitro and in vivo. Specifically, ANXA10 promoted HLA-DR dimers in and on the surface of MSI-H CRC by increasing CD74 expression. Besides, this work demonstrated that ANXA10 contributed to better clinical benefits with anti-PD-1 therapy in MSI-H CRC patients.
Our results provided a novel molecular marker ANXA10 to identify benefit population of MSI-H CRC for improving efficacy of anti-PD-1 and contributed to selection of treatment strategies.
微卫星高度不稳定（MSI-H）的转移性结直肠癌（CRC）患者是免疫检查点阻断治疗的主要人群，然而其中超过一半的患者无法从单药免疫治疗中获益。我们试图鉴定MSI-H CRC的生物标志物，并探索其在抗PD-1治疗中的作用及机制。肿瘤特异性MHC-II与MSI-H CRC对抗PD-1的更好反应相关，且CD74促进HLA-DR二聚体的组装和转运。
通过对来自公共数据集的单细胞和批量转录组测序进行数据分析来筛选特征基因。分别进行将MSI-H CRC细胞与外周血单个核细胞共培养以及在C57BL/6小鼠中建立同基因模型的实验，以检测对抗PD-1治疗的敏感性。
ANXA10被鉴定为MSI-H CRC的特征基因，其在MSI-H CRC中的表达明显高于微卫星稳定（MSS）CRC。ANXA10在体外和体内均显著增强了MSI-H CRC对抗PD-1治疗的敏感性。具体而言，ANXA10通过增加CD74的表达来促进MSI-H CRC细胞内和细胞表面的HLA-DR二聚体形成。此外，本研究表明ANXA10有助于MSI-H CRC患者在接受抗PD-1治疗时获得更好的临床获益。
我们的结果提供了一种新的分子标志物ANXA10，用于识别MSI-H CRC的获益人群，以提高抗PD-1治疗的疗效，并有助于治疗策略的选择。
