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
通用纳米微球筛选技术实现肿瘤治疗中代谢物反应性 T 细胞受体的功能性发现
英文原题：Universal Nanovial Screening Enables Functional Discovery of Metabolite-Reactive T-Cell Receptors for Cancer Therapy.
查看英文原题
Universal Nanovial Screening Enables Functional Discovery of Metabolite-Reactive T-Cell Receptors for Cancer Therapy.
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中文摘要
非常规 T 细胞，包括黏膜相关恒定 T（MAIT）细胞和恒定自然杀伤 T（iNKT）细胞，分别识别由 MR1 和 CD1d 提呈的非肽类抗原，并具有独特的治疗潜力。尽管 TCRα 链恒定，TCRβ 区的多样性可能构成独特的序列-功能关系。
在此，我们开发了一种基于纳米小瓶的功能筛选平台，用于从人血液中存在的非常规 T 细胞中高通量发现 TCR。通过用 MR1 或 CD1d 分子和细胞因子捕获抗体标记纳米小瓶，我们实现了抗原特异性捕获、激活、细胞因子分泌和寡核苷酸条形码连接的鉴定。利用分泌编码的单细胞测序，我们分离出罕见的 MAIT 和 iNKT 细胞，并将其 TCR 身份与功能表型相关联。所有五个 MAIT TCR 在体外均赋予抗原特异性细胞因子分泌和细胞毒性，其中两个在体内测试的 TCR 表现出肿瘤靶向、瘤内积聚和可测量的抗肿瘤活性。
我们的纳米技术赋能的功能优先筛选解锁了非常规 T 细胞的精准 TCR 发现，并支持针对异常代谢通路的疗法开发。
展开英文摘要原文
Unconventional T cells, including mucosal-associated invariant T (MAIT) cells and invariant natural killer T (iNKT) cells, recognize nonpeptide antigens presented by MR1 and CD1d, respectively, and offer unique therapeutic potential. Despite invariant TCRα chains, diversity in TCRβ regions may underlie unique sequence-to-function relationships.
Here, we develop a nanovial-based functional screening platform for the high-throughput discovery of TCRs from unconventional T cells present in human blood. By labeling nanovials with MR1 or CD1d molecules and cytokine-capture antibodies, we enable antigen-specific capture, activation, cytokine secretion, and oligobarcode-linked identification.
Using secretion-encoded single-cell sequencing, we isolate rare MAIT and iNKT cells and associate their TCR identities with functional phenotypes. All five MAIT TCRs conferred antigen-specific cytokine secretion and cytotoxicity in vitro, with the two tested in vivo demonstrating tumor targeting, intratumoral accumulation, and measurable antitumor activity.
Our nanotechnology-enabled "function-first" screen unlocks precision TCR discovery for unconventional T cells and supports the development of therapies targeting aberrant metabolic pathways.
论文信息
- 作者
- Soemardy C、Li YR、Zhu Y、Shen X、Yang L、Di Carlo D
- 单位
- Department of Bioengineering, University of California, Los Angeles, California 90095, United States.United States
- 期刊
- ACS nano2026 Apr 28
- 原文标识
- PubMed 41990155 · DOI 10.1021/acsnano.5c22721