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
FLT3L 依赖性树突状细胞通过调节 Treg 与 NK 细胞稳态调控肿瘤免疫
英文原题：FLT3L-dependent dendritic cells control tumor immunity by modulating Treg and NK cell homeostasis.
查看英文原题
FLT3L-dependent dendritic cells control tumor immunity by modulating Treg and NK cell homeostasis.
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中文摘要
依赖FLT3L的经典树突状细胞（cDC）可募集抗肿瘤及保护肿瘤的淋巴细胞。我们评估了cDC水平低、正常或高的小鼠肿瘤生长情况。出乎意料的是，cDC数量低或高均可改善黑色素瘤小鼠的生存。在cDC低的背景下，适应性免疫系统通过募集效应T细胞并减少Treg和NK细胞，限制肿瘤生长。cDC数量高则促进先天抗肿瘤应答，表现为大量募集活化NK细胞，尽管Treg浸润也较高。抗CTLA-4治疗与FLT3-L治疗联合，在cDC高而非cDC低的背景下具有协同作用；抗PD-1治疗则无此协同。增强cDC并清除Treg联合可显著延长荷瘤小鼠生存期。转录组数据证实，cDC水平对多种人类肿瘤生存具有类似的反常影响。患者中cDC高、Treg低状态预示最佳生存。通过FLT3信号调节cDC数量可能具有治疗人类癌症的潜力。
展开英文摘要原文
FLT3-L-dependent classical dendritic cells (cDCs) recruit anti-tumor and tumor-protecting lymphocytes.
We evaluate cancer growth in mice with low, normal, or high levels of cDCs. Paradoxically, both low or high numbers of cDCs improve survival in mice with melanoma. In low cDC context, tumors are restrained by the adaptive immune system through influx of effector T cells and depletion of Tregs and NK cells. High cDC numbers favor the innate anti-tumor response, with massive recruitment of activated NK cells, despite high Treg infiltration.
Anti CTLA-4 but not anti PD-1 therapy synergizes with FLT3-L therapy in the cDC Hi but not in the cDC Lo context. A combination of cDC boost and Treg depletion dramatically improves survival of tumor-bearing mice. Transcriptomic data confirm the paradoxical effect of cDC levels on survival in several human tumor types. cDC Hi -Treg Lo state in such patients predicts best survival. Modulating cDC numbers via FLT3 signaling may have therapeutic potential in human cancer.
论文信息
- 作者
- Régnier P、Vetillard M、Bansard A、Pierre E、Li X、Cagnard N、Gautier EL、Guermonprez P
- 第一作者单位
- Institut Necker Enfants Malades, INSERM U1151, CNRS UMR-8253, Université Paris Cité, Paris, France; Sorbonne Université, INSERM, UMR_S959, Immunology-Immunopathology-Immunotherapy, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, DMU3ID, Paris, France.France
- 通讯作者单位
- Institut Necker Enfants Malades, INSERM U1151, CNRS UMR-8253, Université Paris Cité, Paris, France; Sorbonne Université, INSERM, UMR_S959, Immunology-Immunopathology-Immunotherapy, Paris, France; Université Paris Cité, Faculté de Médecine, Paris, France. Electronic address: guillaume.darrasse-jeze@inserm.fr.France
- 文献类型
- 非美国政府资助研究
- 期刊
- Cell reports. Medicine2023 Dec 19
- 原文标识
- PubMed 38118422 · DOI 10.1016/j.xcrm.2023.101256
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