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
探究治疗耐药食管肿瘤对 NK 细胞介导的应答的敏感性
英文原题：Investigating the susceptibility of treatment-resistant oesophageal tumours to natural killer cell-mediated responses.
查看英文原题
Investigating the susceptibility of treatment-resistant oesophageal tumours to natural killer cell-mediated responses.
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中文摘要
大多数食管腺癌（OAC）患者对多模式治疗方案无应答，面临极差的生存率。自然杀伤（NK）细胞是关键的抗肿瘤免疫细胞，本研究探讨了治疗耐药的OAC细胞对这些强效肿瘤杀伤细胞的易感性。研究了OE33CisP（顺铂敏感）和OE33CisR（顺铂耐药）细胞的自然杀伤受体（NKR）配体表达。评估了OE33CisP和OE33CisR细胞对NK细胞表型和功能的免疫调节作用。
最后，检测了化疗方案对NKR配体脱落的影响。我们的数据显示，与OE33CisP细胞相比，OE33CisR细胞表面活化性配体B7-H6、MICA/B、ULBP-3以及活化性/抑制性配体PVRL-1和PVRL-4的表达显著降低。与OE33CisR细胞共培养降低了NKp30+和NKp46+ NK细胞的频率，并增加了TIGIT+、FasL+和TRAIL+ NK细胞的频率。与OE33CisP和OE33CisR细胞培养后，产生IFN-的NK细胞频率增加，而TIM-3+ NK细胞频率降低。在治疗反应最差的OAC患者和接受FLOT化疗的患者中，循环NKp30+ NK细胞的频率显著降低，而FLOT可诱导OAC肿瘤细胞B7-H6脱落。
总体而言，OE33CisR细胞表达的活化性NKR配体少于OE33CisP细胞，并对NK细胞的NKR表达具有差异性影响。然而，两种细胞系均未显著抑制NK细胞因子产生、死亡受体表达或脱颗粒。
此外，我们的数据表明，FLOT化疗可能促进B7-H6脱落和免疫逃逸，对OAC患者产生不利后果。
展开英文摘要原文
The majority of oesophageal adenocarcinoma (OAC) patients do not respond to multimodal treatment regimens and face dismal survival rates. Natural killer (NK) cells are crucial anti-tumour immune cells, and this study investigated the susceptibility of treatment-resistant OAC cells to these potent tumour killers.
Natural killer receptor (NKR) ligand expression by OE33CisP (cisplatin-sensitive) and OE33CisR (cisplatin-resistant) cells was investigated. The immunomodulatory effects of OE33CisP and OE33CisR cells on NK cell phenotype and function were assessed.
Finally, the impact of chemotherapy regimens on NKR ligand shedding was examined.
Our data revealed significantly less surface expression of activating ligands B7-H6, MICA/B, ULBP-3 and activating/inhibitory ligands PVRL-1 and PVRL-4 by OE33CisR cells, compared to OE33CisP cells. Co-culture with OE33CisR cells reduced the frequencies of NKp30 + and NKp46 + NK cells and increased frequencies of TIGIT + , FasL + and TRAIL + NK cells.
Frequencies of IFN- -producing NK cells increased while frequencies of TIM-3 + NK cells decreased after culture with OE33CisP and OE33CisR cells. Frequencies of circulating NKp30 + NK cells were significantly lower in OAC patients with the poorest treatment response and in patients who received FLOT chemotherapy, while B7-H6 shedding by OAC tumour cells was induced by FLOT.
Overall, OE33CisR cells express less activating NKR ligands than OE33CisP cells and have differential effects on NKR expression by NK cells.
However, neither cell line significantly dampened NK cell cytokine production, death receptor expression or degranulation.
In addition, our data indicate that FLOT chemotherapy may promote B7-H6 shedding and immune evasion with detrimental consequences in OAC patients.
论文信息
- 作者
- Mylod E、McKenna E、Davern M、Barr MP、Donlon NE、Bibby BAS、Bhardwaj A、Reynolds JV
- 第一作者单位
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland.Ireland
- 通讯作者单位
- Cancer Immunology and Immunotherapy Group, Department of Surgery, Trinity Translational Medicine Institute and Trinity St. James's Cancer Institute, St. James's Hospital, Trinity College Dublin, Dublin 8, Ireland. meconroy@tcd.ie.Ireland
- 期刊
- Clinical and experimental medicine2023 Jun
- 原文标识
- PubMed 35364779 · DOI 10.1007/s10238-022-00811-6
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