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
英文原题:BCG priming followed by a novel interleukin combination activates Natural Killer cells to selectively proliferate and become anti-tumour long-lived effectors.
BCG priming followed by a novel interleukin combination activates Natural Killer cells to selectively proliferate and become anti-tumour long-lived effectors.
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自然杀伤(NK)细胞的短寿命和异质性限制了基于NK细胞的疗法的发展,尽管其抗肿瘤的安全性和有效性已得到证实。在此,我们描述了在卡介苗(BCG)预处理外周血细胞后,无需细胞分选或饲养层细胞即可获得的長寿命抗肿瘤人NK细胞(CD56高CD16+)的生物学基础、详细表型和功能。此外,我们证明,每周仅给予一次排除IL18的细胞因子组合的存活剂量于BCG预处理的NK细胞,可避免先天淋巴细胞耗竭,并导致先天细胞的特异性长期增殖,这些细胞主要通过NKG2D对多种实体瘤发挥强效细胞毒性功能。引人注目的是,在BCG和细胞因子刺激后,一个NKG2C+CD57-FcεRIγ+NK细胞群体扩增,且不依赖于HCMV血清学状态。该策略被用于从癌症患者骨髓的抑制环境中拯救抗肿瘤NK细胞,证明BCG赋予NK细胞持久的抗肿瘤特征。
The short-lived nature and heterogeneity of Natural Killer (NK) cells limit the development of NK cell-based therapies, despite their proven safety and efficacy against cancer.
Here, we describe the biological basis, detailed phenotype and function of long-lived anti-tumour human NK cells (CD56 high CD16 + ), obtained without cell sorting or feeder cells, after priming of peripheral blood cells with Bacillus Calmette-Guérin (BCG).
Further, we demonstrate that survival doses of a cytokine combination, excluding IL18, administered just weekly to BCG-primed NK cells avoids innate lymphocyte exhaustion and leads to specific long-term proliferation of innate cells that exert potent cytotoxic function against a broad range of solid tumours, mainly through NKG2D.
Strikingly, a NKG2C + CD57 - FcεRIγ + NK cell population expands after BCG and cytokine stimulation, independently of HCMV serology. This strategy was exploited to rescue anti-tumour NK cells even from the suppressor environment of cancer patients' bone marrow, demonstrating that BCG confers durable anti-tumour features to NK cells.
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