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
通过重新接合免疫突触分子增强抗肿瘤免疫
英文原题：Potentiating anti-tumor immunity by re-engaging immune synapse molecules.
查看英文原题
Potentiating anti-tumor immunity by re-engaging immune synapse molecules.
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中文摘要
细胞毒性T细胞与肿瘤细胞之间免疫突触（IS）的形成对于有效清除肿瘤至关重要。然而，IS在免疫逃逸和对免疫检查点阻断（ICB）耐药中的作用仍不清楚。我们证明，ICAM-1——一种激活T细胞和自然杀伤（NK）细胞中LFA-1信号的关键IS分子——在癌症中常呈低水平表达。ICAM-1的缺失导致对T细胞和NK细胞介导的抗肿瘤免疫产生显著耐药。通过CRISPR筛选，我们发现ICAM-1受涉及UHRF1和DNMT1的DNA甲基化通路表观遗传调控。此外，我们设计了一种基于抗体的治疗剂——"LFA-1 engager"，通过重建LFA-1信号来增强T细胞介导的抗肿瘤免疫。在ICAM-1缺陷肿瘤的小鼠模型中，LFA-1 engager治疗可显著增强免疫介导的细胞毒性、增强抗肿瘤免疫，并与ICB产生协同作用。我们的数据为在癌症免疫治疗中重新激活免疫刺激信号提供了有前景的治疗策略。
展开英文摘要原文
The formation of immune synapses (ISs) between cytotoxic T cells and tumor cells is crucial for effective tumor elimination.
However, the role of ISs in immune evasion and resistance to immune checkpoint blockades (ICBs) remains unclear.
We demonstrate that ICAM-1, a key IS molecule activating LFA-1 signaling in T and natural killer (NK) cells, is often expressed at low levels in cancers. The absence of ICAM-1 leads to significant resistance to T and NK cell-mediated anti-tumor immunity. Using a CRISPR screen, we show that ICAM-1 is epigenetically regulated by the DNA methylation pathway involving UHRF1 and DNMT1.
Furthermore, we engineer an antibody-based therapeutic agent, "LFA-1 engager," to enhance T cell-mediated anti-tumor immunity by reconstituting LFA-1 signaling. Treatment with LFA-1 engagers substantially enhances immune-mediated cytotoxicity, potentiates anti-tumor immunity, and synergizes with ICB in mouse models of ICAM-1-deficient tumors.
Our data provide promising therapeutic strategies for re-engaging immune stimulatory signals in cancer immunotherapy.
论文信息
- 作者
- Zhou X、Xu T、Li C、He Y、Hu Y、Gong H、Li J、Jiang H
- 第一作者单位
- State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.China
- 通讯作者单位
- State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Science (CLS), Beijing 100084, China. Electronic address: dpan@tsinghua.edu.cn.China
- 期刊
- Cell reports. Medicine2025 Mar 18
- 原文标识
- PubMed 39999838 · DOI 10.1016/j.xcrm.2025.101975
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