Zhou Xindi, Xu Tian, Li Changhe, He Yufeng, Hu Yuanzhi, Gong Hao, Li Jiahui, Jiang Haitao, Wen Liang, Fu Yangxin, Zeng Zexian, Pan Deng
State Key Laboratory of Molecular Oncology, School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China.
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Cell Rep Med. 2025 Mar 18;6(3):101975. doi: 10.1016/j.xcrm.2025.101975. Epub 2025 Feb 24.
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.
细胞毒性T细胞与肿瘤细胞之间免疫突触（ISs）的形成对于有效消除肿瘤至关重要。然而，ISs在免疫逃逸和对免疫检查点阻断（ICB）的抗性中的作用仍不清楚。我们证明，ICAM-1是一种在T细胞和自然杀伤（NK）细胞中激活LFA-1信号的关键IS分子，在癌症中通常低水平表达。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抗性。通过CRISPR筛选，我们表明ICAM-1受涉及UHRF1和DNMT1的DNA甲基化途径的表观遗传调控。此外，我们设计了一种基于抗体的治疗剂“LFA-1衔接子”，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，用LFA-1衔接子治疗可显著增强免疫介导的细胞毒性，增强抗肿瘤免疫力，并与ICB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。
