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:Mucosal-associated invariant T cells modulate innate immune cells and inhibit colon cancer growth.
Mucosal-associated invariant T cells modulate innate immune cells and inhibit colon cancer growth.
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黏膜相关恒定T(MAIT)细胞是一类先天性样T细胞,可由微生物抗原和细胞因子激活,在包括结肠在内的黏膜组织中含量丰富。MAIT细胞具有细胞毒性和促炎功能,具有用作过继性细胞治疗的潜力。
然而,关于其抗癌活性,包括在结肠癌中的作用的研究有限。利用结肠癌动物模型,我们发现,与对照组相比,将体内扩增的MAIT细胞瘤周注射到携带MC38衍生肿瘤的RAG1 -/- 小鼠中可抑制肿瘤生长。多重细胞因子分析显示,MAIT细胞治疗组的肿瘤中嗜酸性粒细胞活化细胞因子的标志物表达更高,提示嗜酸性粒细胞募集与肿瘤抑制之间可能存在关联。在人外周白细胞共培养模型中,我们发现,用MAIT配体刺激的白细胞显示eotaxin-1产生增加和嗜酸性粒细胞活化,并与癌细胞杀伤增加相关。
总之,我们发现在小鼠结肠癌模型中MAIT细胞具有保护作用,这与对癌症免疫应答的调节相关,可能涉及嗜酸性粒细胞相关机制。我们的结果凸显了MAIT细胞用于非供者限制性结肠癌免疫治疗的潜力。
Mucosal-associated invariant T (MAIT) cells are innate-like T cells that can be activated by microbial antigens and cytokines and are abundant in mucosal tissues including the colon. MAIT cells have cytotoxic and pro-inflammatory functions and have potentials for use as adoptive cell therapy.
However, studies into their anti-cancer activity, including their role in colon cancer, are limited. Using an animal model of colon cancer, we showed that peritumoral injection of in vivo-expanded MAIT cells into RAG1 -/- mice with MC38-derived tumours inhibits tumour growth compared to control.
Multiplex cytokine analyses showed that tumours from the MAIT cell-treated group have higher expression of markers for eosinophil-activating cytokines, suggesting a potential association between eosinophil recruitment and tumour inhibition. In a human peripheral leukocyte co-culture model, we showed that leukocytes stimulated with MAIT ligand showed an increase in eotaxin-1 production and activation of eosinophils, associated with increased cancer cell killing.
In conclusion, we showed that MAIT cells have a protective role in a murine colon cancer model, associated with modulation of the immune response to cancer, potentially involving eosinophil-associated mechanisms.
Our results highlight the potential of MAIT cells for non-donor restricted colon cancer immunotherapy.
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