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
合成免疫检查点衔接分子保护 HLA 缺陷型 iPSCs 及其衍生细胞免受先天免疫细胞细胞毒性
英文原题：Synthetic immune checkpoint engagers protect HLA-deficient iPSCs and derivatives from innate immune cell cytotoxicity.
查看英文原题
Synthetic immune checkpoint engagers protect HLA-deficient iPSCs and derivatives from innate immune cell cytotoxicity.
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中文摘要
同种异体细胞治疗的免疫排斥仍是免疫肿瘤学和再生医学的主要问题。迄今为止，与自体替代方案相比，同种异体细胞产品的持久性和疗效较差。低免疫原性细胞的工程化改造可能大幅提高其治疗获益。我们提出了一类新型激动性免疫检查点衔接分子，可保护人类白细胞抗原（HLA）缺失的诱导多能干细胞来源的内皮细胞（iECs）免受先天免疫细胞的攻击。对其抑制性受体 TIM3 和 SIRPα 具有激动功能的衔接分子可有效保护工程化 iECs 免受自然杀伤（NK）细胞和巨噬细胞的杀伤。SIRPα 衔接分子可与截短的 CD64 组合，生成完全免疫逃逸的 iECs，能够逃避同种异体细胞和免疫球蛋白 G（IgG）抗体介导的排斥。合成免疫检查点衔接分子具有高靶点特异性，且在工程化细胞中缺乏逆行信号传导。这种模块化设计允许利用更多抑制性免疫通路来实现免疫逃逸，并可能促进同种异体细胞治疗的发展。
展开英文摘要原文
Immune rejection of allogeneic cell therapeutics remains a major problem for immuno-oncology and regenerative medicine. Allogeneic cell products so far have inferior persistence and efficacy when compared with autologous alternatives. Engineering of hypoimmune cells may greatly improve their therapeutic benefit.
We present a new class of agonistic immune checkpoint engagers that protect human leukocyte antigen (HLA)-depleted induced pluripotent stem cell-derived endothelial cells (iECs) from innate immune cells. Engagers with agonistic functionality to their inhibitory receptors TIM3 and SIRPα effectively protect engineered iECs from natural killer (NK) cell and macrophage killing.
The SIRPα engager can be combined with truncated CD64 to generate fully immune evasive iECs capable of escaping allogeneic cellular and immunoglobulin G (IgG) antibody-mediated rejection. Synthetic immune checkpoint engagers have high target specificity and lack retrograde signaling in the engineered cells. This modular design allows for the exploitation of more inhibitory immune pathways for immune evasion and could contribute to the advancement of allogeneic cell therapeutics.
论文信息
- 作者
- Gravina A、Tediashvili G、Zheng Y、Iwabuchi KA、Peyrot SM、Roodsari SZ、Gargiulo L、Kaneko S
- 第一作者单位
- Transplant and Stem Cell Immunobiology (TSI)-Lab, Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA.United States
- 通讯作者单位
- Transplant and Stem Cell Immunobiology (TSI)-Lab, Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA. Electronic address: tobias.deuse@ucsf.edu.United States
- 期刊
- Cell stem cell2023 Nov 2
- 原文标识
- PubMed 37922880 · DOI 10.1016/j.stem.2023.10.003