醛脱氢酶 1 高的癌症干细胞/癌症起始细胞由于人类白细胞抗原类 1 表达降低而逃避细胞毒性 T 淋巴细胞。
Aldehyde Dehydrogenese-1 High Cancer Stem-like Cells/Cancer-initiating Cells Escape from Cytotoxic T Lymphocytes due to Lower Expression of Human Leukocyte Antigen Class 1.
机构信息
Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
Department of Gastroenterological Surgery II, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
出版信息
Anticancer Res. 2024 May;44(5):1877-1883. doi: 10.21873/anticanres.16989.
BACKGROUND/AIM: Human gastric cancer stem-like cells (CSCs)/cancer-initiating cells can be identified as aldehyde dehydrogenase-high (ALDH) cells. Cancer immunotherapy employing immune checkpoint blockade has been approved for advanced gastric cancer cases. However, the effectiveness of cancer immunotherapy against gastric CSCs/CICs remains unclear. This study aimed to investigate the susceptibility of gastric CSCs/CICs to immunotherapy.
MATERIALS AND METHODS
Gastric CSCs/CICs were isolated as ALDH cells using the human gastric cancer cell line, MKN-45. ALDH clone cells and ALDH clone cells were isolated using the ALDEFLUOR assay. ALDH1A1 expression was assessed via qRT-PCR. Sphere-forming ability was evaluated to confirm the presence of CSCs/CICs. A model neoantigen, AP2S1, was over-expressed in ALDH clone cells and ALDH clone cells, and susceptibility to AP2S1-specific TCR-T cells was assessed using IFNγ ELISPOT assay.
RESULTS
Three ALDH clone cells were isolated from MKN-45 cells. ALDH clone cells exhibited a stable phenotype in in vitro culture for more than 2 months. The High-36 clone cells demonstrated the highest sphere-forming ability, whereas the Low-8 cells showed the lowest sphere-forming ability. High-36 cells exhibited lower expression of HLA-A24 compared to Low-8 cells. TCR-T cells specific for AP2S1 showed lower reactivity to High-36 cells compared to Low-8 cells.
CONCLUSION
High-36 cells and Low-8 cells represent novel gastric CSCs/CICs and non-CSCs/CICs, respectively. ALDH CSCs/CICs evade T cells due to lower expression of HLA class 1.
背景/目的：人类胃癌干细胞样细胞（CSCs）/起始细胞可被鉴定为乙醛脱氢酶高（ALDH）细胞。免疫检查点阻断的癌症免疫疗法已被批准用于晚期胃癌病例。然而，针对胃癌 CSCs/CIC 的癌症免疫疗法的效果仍不清楚。本研究旨在探讨胃癌 CSCs/CIC 对免疫疗法的敏感性。
材料和方法
使用人胃癌细胞系 MKN-45 通过 ALDH 细胞分离法分离胃癌 CSCs/CIC。使用 ALDEFLUOR 测定法分离 ALDH 克隆细胞和 ALDH 克隆细胞。通过 qRT-PCR 评估 ALDH1A1 表达。通过球形成能力评估确认 CSCs/CIC 的存在。在 ALDH 克隆细胞和 ALDH 克隆细胞中过表达模型新抗原 AP2S1，并通过 IFNγ ELISPOT 测定评估 AP2S1 特异性 TCR-T 细胞的敏感性。
结果
从 MKN-45 细胞中分离出三个 ALDH 克隆细胞。ALDH 克隆细胞在体外培养中表现出超过 2 个月的稳定表型。High-36 克隆细胞具有最高的球体形成能力，而 Low-8 细胞的球体形成能力最低。High-36 细胞与 Low-8 细胞相比，HLA-A24 的表达较低。针对 AP2S1 的 TCR-T 细胞对 High-36 细胞的反应性低于对 Low-8 细胞的反应性。
结论
High-36 细胞和 Low-8 细胞分别代表新型胃癌 CSCs/CIC 和非 CSCs/CIC。ALDH CSCs/CIC 由于 HLA 类 1 的表达较低而逃避 T 细胞。
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