RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
CT45A1 介导的 MLC2 (MYL9) 磷酸化促进细胞叠入结构中的 NK 细胞抵抗和外层细胞命运，从而增强微卫星高度不稳定结直肠癌的进展
英文原题：CT45A1-mediated MLC2 (MYL9) phosphorylation promotes natural killer cell resistance and outer cell fate in a cell-in-cell structure, potentiating the progression of microsatellite instability-high colorectal cancer.
查看英文原题
CT45A1-mediated MLC2 (MYL9) phosphorylation promotes natural killer cell resistance and outer cell fate in a cell-in-cell structure, potentiating the progression of microsatellite instability-high colorectal cancer.
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中文摘要
微卫星高度不稳定（MSI-H）结直肠癌（CRC）患者具有高肿瘤突变负荷和肿瘤免疫原性，对免疫治疗表现出更高的缓解率和更好的生存。
然而，一部分MSI-H CRC患者仍经历不良的疾病结局。我们旨在鉴定决定这些异质性临床结局的肿瘤自主调控因子。使用癌症基因组图谱（TCGA）数据集鉴定预后不良的MSI-H CRC患者中的调控因子。建立表达目标调控因子的稳定CRC肿瘤克隆，以评估迁移和干性特性、免疫细胞易感性以及细胞套细胞（CIC）结构形成。使用RNA测序（RNA-seq）鉴定稳定CRC肿瘤克隆中富集的生物学通路。对福尔马林固定石蜡包埋（FFPE）的MSI-H CRC标本进行临床病理学表征，以探索所涉及的潜在机制。
我们发现，在生存结局较差的MSI-H CRC患者中，癌/睾丸抗原家族45成员A1（CT45A1）表达上调。表达CT45A1的微卫星稳定（MSS）CRC细胞表现出增强的迁移能力。
然而，表达CT45A1的MSI-H CRC细胞，而非MSS CRC细胞，表现出对自然杀伤（NK）细胞细胞毒性更高的抵抗性，并在同型CIC结构中充当外层细胞，阻止外源性或治疗性抗体接近内层CRC细胞。使用小分子抑制剂或靶向肌球蛋白轻链激酶（MYLK）的短发夹RNA（shRNA）失活RHO-ROCK/MLCK-MLC2信号通路，可消除NK细胞抵抗性并减少表达CT45A1的MSI-H CRC细胞的外层细胞命运。在MSI-H CRC患者中，CT45A1阳性肿瘤表现出MLC2磷酸化增加、外细胞命运增加以及生存率降低。
我们证明CT45A1促进了MSI-H CRC的晚期进展，靶向MLC2磷酸化可能增强CT45A1阳性MSI-H CRC患者的免疫治疗疗效。
展开英文摘要原文
Patients with microsatellite instability-high (MSI-H) colorectal cancer (CRC) have high tumor mutation burden and tumor immunogenicity, exhibiting a higher response rate to immunotherapy and better survival.
However, a portion of MSI-H CRC patients still experience adverse disease outcomes.
We aimed to identify the tumor-autonomous regulators determining these heterogeneous clinical outcomes. The Cancer Genome Atlas (TCGA) dataset was used to identify regulators in MSI-H CRC patients with unfavorable outcomes. Stable CRC tumor clones expressing targeted regulators were established to evaluate migratory and stemness properties, immune cell vulnerability, and cell-in-cell (CIC) structure formation.
RNA-sequencing (RNA-seq) was used to identify enriched biological pathways in stable CRC tumor clones. Clinicopathological characterization of formalin-fixed paraffin-embedded (FFPE) MSI-H CRC specimens was performed to explore the underlying mechanisms involved.
We showed that cancer/testis antigen family 45 member A1 (CT45A1) expression was upregulated in MSI-H CRC patients with poor survival outcomes. CT45A1-expressing microsatellite stable (MSS) CRC cells showed enhanced migratory ability.
However, CT45A1-expressing MSI-H CRC cells, but not MSS CRC cells, showed higher resistance to natural killer (NK) cell cytotoxicity and served as outer cells in homotypic CIC structures, preventing exogenous or therapeutic antibody access to inner CRC cells.
Inactivating RHO-ROCK/MLCK-MLC2 signaling with small-molecule inhibitors or short-hairpin RNAs (shRNAs) targeting myosin light chain kinase (MYLK) abolished NK cell resistance and reduced the outer cell fate of CT45A1-expressing MSI-H CRC cells. In MSI-H CRC patients, CT45A1-positive tumors exhibited increased MLC2 phosphorylation, increased outer cell fate, and decreased survival.
We demonstrated that CT45A1 potentiates the advanced progression of MSI-H CRC, and targeting MLC2 phosphorylation may enhance immunotherapy efficacy in CT45A1-positive MSI-H CRC patients.
论文信息
- 作者
- Teng HW、Huang HY、Lin CC、Twu YC、Yang WH、Lin WC、Lan HY、Lin YY
- 第一作者单位
- Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taiwan.Taiwan
- 通讯作者单位
- Department of Biotechnology and Laboratory Science in Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan.Taiwan
- 期刊
- Molecular oncology2025 Feb
- 原文标识
- PubMed 39322998 · DOI 10.1002/1878-0261.13736
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