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
23ME-01473，一种 Fc 效应增强的抗 ULBP6/2/5 抗体，通过 NKG2D 和 FcγRIIIa 激活恢复 NK 细胞介导的抗肿瘤免疫
英文原题：23ME-01473, an Fc Effector-Enhanced Anti-ULBP6/2/5 Antibody, Restores NK Cell-Mediated Antitumor Immunity through NKG2D and FcγRIIIa Activation.
查看英文原题
23ME-01473, an Fc Effector-Enhanced Anti-ULBP6/2/5 Antibody, Restores NK Cell-Mediated Antitumor Immunity through NKG2D and FcγRIIIa Activation.
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中文摘要
摘要：免疫检查点抑制剂改变了癌症治疗格局，但许多患者仍无法获益，因此需要寻找有希望的新靶点以实施更有效干预。本研究利用 23andMe, Inc. 大规模人类生殖系遗传与健康数据库，揭示此前未知的 UL16 结合蛋白 6（ULBP6）在癌症中的作用；ULBP6 是高亲和力 NK 细胞受体 NKG2D 的配体，也是有潜力的肿瘤免疫治疗靶点。研究者确认 ULBP6 在人类肿瘤中表达，并证明从肿瘤脱落的可溶性 ULBP6 会绕过膜锚定 NKG2D 配体所提供的 NKG2D 激活信号，从而抑制免疫细胞活化和肿瘤细胞杀伤。基于这些发现，研究者开发了 23ME-01473，这是一种人源化、增强 Fc 效应功能的抗体，可结合 ULBP6 及其近缘家族成员 ULBP2 和 ULBP5。23ME-01473 可有效阻断可溶性 ULBP6 介导的免疫抑制，恢复 NK 细胞和 T 细胞的 NKG2D 轴功能，控制肿瘤生长。此外，23ME-01473 的 Fc 效应功能增强设计提高了其对 FcγRIIIa 的结合亲和力；结合其与癌细胞膜锚定 ULBP6/2/5 的能力，可增强抗体依赖性细胞毒作用，为 NK 细胞提供第二个激活节点。研究显示，增强 Fc 效应功能的抗 ULBP6/2/5 抗体具有治疗潜力，可恢复 NK 细胞和 T 细胞的活化及细胞毒作用，用于癌症治疗。意义：本研究强调基于人群的全基因组评估有助于发现与癌症或免疫疾病终生风险相关的自然遗传变异，并识别新药物靶点。研究确定 ULBP6 可能是 NKG2D 通路的关键成员，而该通路对抗肿瘤免疫至关重要。靶向 ULBP6 可能为癌症患者带来治疗希望。
展开英文摘要原文
ABSTRACT: The landscape of cancer treatment has been transformed by immune checkpoint inhibitors; however, the failure to benefit a large number of patients with cancer has underlined the need to identify promising targets for more effective interventions. In this study, we leverage 23andMe, Inc. s large-scale human germline genetic and health database to uncover the previously unknown role of UL16-binding protein 6 (ULBP6), a high-affinity NK group 2D (NKG2D) ligand, in cancer and its promise as an immuno-oncology therapeutic target.
We confirm ULBP6 expression in human tumors and demonstrate that soluble ULBP6 shed from tumors circumvents NKG2D activation provided by membrane-anchored NKG2D ligands to inhibit immune cell activation and tumor cell killing. Based on these findings, we developed 23ME-01473, a humanized Fc effector enhanced antibody that binds to ULBP6 and its closely related family members, ULBP2 and ULBP5. 23ME-01473 effectively blocks soluble ULBP6-mediated immunosuppression to restore the NKG2D axis on NK and T cells to elicit tumor growth control.
Moreover, the Fc effector enhanced design of 23ME-01473 increases its binding affinity to fragment crystallizable gamma receptor IIIa, which, together with 23ME-01473 s binding to membrane-anchored ULBP6/2/5 on cancer cells, allows for augmented antibody-dependent cellular cytotoxicity induction, providing a second activation node for NK cells.
Our studies demonstrate the therapeutic potential of an Fc effector enhanced anti-ULBP6/2/5 antibody to reinvigorate NK cell and T-cell activation and cytotoxicity for the treatment of cancer. SIGNIFICANCE: This study emphasizes the utility of population-based genome-wide assessments for discovering naturally occurring genetic variants associated with lifetime risks for cancer or immune diseases as novel drug targets.
We identify ULBP6 as a potential keystone member of the NKG2D pathway, which is important for antitumor immunity. Targeting ULBP6 may hold therapeutic promise for patients with cancer.
论文信息
- 作者
- Benjamin JS、Jarret A、Bharill S、Fontanillas P、23andMe Research Team、Yadav S、Sen D、Ayupova D
- 单位
- 23andMe, Inc. Therapeutics, South San Francisco, California.United States
- 文献类型
- 非美国政府资助研究
- 期刊
- Cancer research communications2025 Mar 1
- 原文标识
- PubMed 40116579 · DOI 10.1158/2767-9764.CRC-24-0478
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