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
死亡受体 4/5 介导错配修复缺陷结直肠癌对 NK 细胞介导细胞毒性的敏感性
英文原题：Death receptors 4/5 mediate tumour sensitivity to natural killer cell-mediated cytotoxicity in mismatch repair deficient colorectal cancer.
查看英文原题
Death receptors 4/5 mediate tumour sensitivity to natural killer cell-mediated cytotoxicity in mismatch repair deficient colorectal cancer.
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研究概要
dMMR 与结直肠癌中对 NK 细胞介导的细胞毒性敏感性增高相关。
中文摘要
背景
确定自然杀伤（NK）细胞在结直肠癌（CRC）中的靶点，对于优化 NK 细胞介导免疫疗法的临床应用至关重要。错配修复缺陷（dMMR）与免疫细胞浸润较高及 MHC I 类分子缺陷相关，但 dMMR CRC 是否对 NK 细胞疗法有反应仍不清楚。
方法
采用 CRISPR-Cas9 系统建立 MLH1、DR4 和 DR5 敲除细胞系。使用 NK92-MI 细胞或从 BALB/C 小鼠分离的 NK 细胞作为效应细胞，靶向肿瘤细胞。通过细胞因子分析评估 CRC 细胞分泌炎症性细胞因子的情况，并采用 NK 细胞缺失或功能完整的动物模型验证 NK 细胞敏感性。
结果
与错配修复功能完整（pMMR）的 CRC 细胞相比，dMMR CRC 细胞对 NK 细胞介导的细胞毒作用更敏感。在 dMMR CRC 中，死亡受体 DR4/5 上调并介导了对 NK 细胞细胞毒作用的敏感性。DR4/5 介导的白细胞介素 12 分泌可维持 dMMR CRC 中 NK 细胞的活性。耗竭 NK 细胞会促进 dMMR CRC 肿瘤生长；在体内，转移 NK 细胞可抑制表达 DR4/5 的 dMMR CRC 肺转移。TP53 可上调 dMMR CRC 中 DR4/DR5 的表达。
结论
dMMR 与 CRC 对 NK 细胞介导细胞毒作用的敏感性增加相关；DR4/DR5 可使 dMMR CRC 对 NK 细胞细胞毒作用更敏感。
展开英文摘要原文
BACKGROUND
Identifying the target of natural killer (NK) cells in colorectal cancer (CRC) is critical for optimising the clinical use of NK cell-mediated immunotherapy. Mismatch repair deficiency (dMMR) is associated with high immune cell infiltration and MHC Class I defects. Whether dMMR CRC responses to NK cell therapy remains unclear.
METHODS
MLH1, DR4, and DR5 knockout cell lines were established using CRISPR-Cas9 system. NK92-MI or NK cell isolated from BABL/C mice were used as effector cells against tumour cells. Inflammatory cytokines secretion by CRC cells was assessed via cytokine analysis. NK-cell-deficient/proficient animal models were used to validate the NK cell sensitivity.
RESULTS
We observed that dMMR CRC cells were more sensitive to NK cell-mediated cytotoxicity than were mismatch-repair-proficient (pMMR) CRC cells. In dMMR CRC, Death receptor (DR)4/5 was upregulated and mediated sensitivity to NK cell-mediated cytotoxicity. DR4/5-mediated secretion of interleukin -12 sustained NK cell viability in dMMR CRC. NK cell depletion induced dMMR CRC tumour growth, and NK cell transfer inhibited lung metastasis of dMMR CRC with DR4/5 expression in vivo. TP53 upregulated DR4/DR5 expression in dMMR CRC.
CONCLUSIONS
dMMR associated with increased sensitivity to NK cell-mediated cytotoxicity in CRC. DR4/DR5 sensitise dMMR CRC to NK cell-mediated cytotoxicity.
论文信息
- 作者
- Yang L、Yi J、He W、Kong P、Xie Q、Jin Y、Xiong Z、Xia L
- 第一作者单位
- Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China.China
- 通讯作者单位
- Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China. xialp@sysucc.org.cn.China
- 期刊
- British journal of cancer2024 Jul
- 原文标识
- PubMed 38796599 · DOI 10.1038/s41416-024-02673-z
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