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
多功能工程化 NK 细胞通过结合 PD-L1 和 HLA-E 靶向及内源性 IL15 产生克服肿瘤免疫抑制
英文原题：Multifunctional-engineered NK cells overcome tumor immunosuppression by combining PD-L1 and HLA-E targeting and endogenous IL15 production.
查看英文原题
Multifunctional-engineered NK cells overcome tumor immunosuppression by combining PD-L1 and HLA-E targeting and endogenous IL15 production.
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中文摘要
免疫抑制性肿瘤微环境（TME）对有效的肿瘤免疫治疗构成重大挑战，因为它通过冗余检查点通路、代谢限制和直接抑制效应细胞使肿瘤得以逃逸。为克服这些障碍，我们开发了一种下一代 NK 细胞平台，使用三顺反子逆转录病毒载体增强 NK 细胞活化、募集、存活和代谢适应性。泛癌转录组分析显示，PD-L1 和 HLA-E 在肿瘤中一致共表达，这与伴随强烈免疫抑制的免疫浸润相关，突出这些分子是免疫逃逸的关键靶点。为改善 TME 中 NK 细胞的募集、活化、细胞溶解功能、存活和代谢适应性，我们开发了一种下一代 NK 细胞平台，使用三顺反子逆转录病毒载体，其编码一个胞外 PD-1 结构域（ex PD1），该结构域与带有共刺激分子 4-1BB 的 NKG2D 胞内部分融合，并表达可溶性 IL15 和 NKG2A 单链可变片段（scFv）。
因此，ex PD1 允许识别表达 PD-L1 的细胞，而胞内共刺激信号将抑制性相互作用 PD-1/PD-L1 转化为激活性相互作用。该策略有效靶向 PD-L1 阳性肿瘤细胞，并在原本阴性的肿瘤中诱导从头 PD-L1 表达。为进一步增强抗肿瘤活性，我们引入了一个编码可溶性 NKG2A-scFv 的模块，以遮蔽 NK 细胞上的 NKG2A 受体并阻碍 NKG2A/HLA-E 抑制性相互作用。
此外，我们通过递送受控的低剂量 IL15 改善了 NK 细胞存活和扩增，这可防止 NK 细胞耗竭并延长其在体内的存在。这一整合策略可能提供一种新型、即用型异体成熟NK细胞疗法，能够克服检查点介导的抑制、代谢抑制和免疫逃逸，为治疗高危和难治性肿瘤提供有前景的模式。
展开英文摘要原文
The immunosuppressive tumor microenvironment (TME) poses a significant challenge to effective cancer immunotherapy, as it enables tumor escape through redundant checkpoint pathways, metabolic constraints, and direct inhibition of effector cells. To overcome these barriers, we developed a next-generation NK cell platform using a tri-cistronic retroviral vector that enhances NK cell activation, recruitment, survival, and metabolic fitness.
Pan-cancer transcriptomic analyses reveal consistent co-expression of PD-L1 and HLA-E across tumors, which correlates with immune infiltration accompanied by strong immunosuppression, highlighting these molecules as key targets for immune evasion.
To improve NK cell recruitment, activation, cytolytic function, survival, and metabolic fitness in the TME, we developed a next-generation NK cell platform using a tri-cistronic retroviral vector that encodes an extracellular PD-1 domain ( ex PD1) fused to the intracellular portion of NKG2D with the costimulatory molecule 4-1BB, and expressing soluble IL15 and NKG2A single-chain variable fragments (scFv).
Thus, the ex PD1 allows the recognition of cells expressing PD-L1, while the intracellular costimulatory signaling transforms the inhibitory interaction PD-1/PD-L1 into an activating one. This strategy effectively targets PD-L1-positive tumor cells and induces de novo PD-L1 expression in otherwise negative tumors. To further enhance anti-tumor activity, we incorporated a module encoding soluble NKG2A-scFv to mask the NKG2A receptor on NK cells and hinder NKG2A/HLA-E inhibitory interaction.
Additionally, we improved NK cell survival and expansion by delivering controlled low doses of IL15, which prevents NK cell exhaustion and extends their presence in vivo. This integrated strategy may provide a novel, ready-to-use allogenic mature NK cell therapy that could overcome checkpoint-mediated inhibition, metabolic suppression, and immune escape, offering a promising model for treating high-risk and treatment-resistant tumors.
论文信息
- 作者
- Fiore PF、Forcelloni S、Moretta L、Assenza MR、Orecchia P、Bilotta MT、Machwirth M、Shpati T
- 第一作者单位
- Innate Lymphoid Cells Unit, Immunology Research Area, Bambino Gesù Children's Hospital IRCCS, Rome, Italy.Italy
- 通讯作者单位
- Innate Lymphoid Cells Unit, Immunology Research Area, Bambino Gesù Children's Hospital IRCCS, Rome, Italy. paola.vacca@opbg.net.Italy
- 期刊
- Signal transduction and targeted therapy2026 Jul 10
- 原文标识
- PubMed 42425951 · DOI 10.1038/s41392-026-02827-w
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