Huerta-Yepez Sara, Chen Po-Chun, Kaur Kawaljit, Jain Yash, Singh Tanya, Esedebe Favour, Liao Yi Jou, DiBernardo Gabriella, Moatamed Neda A, Mei Ao, Malarkannan Subramaniam, Graeber Thomas G, Memarzadeh Sanaz, Jewett Anahid
Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, University of California School of Dentistry, Le Conte Ave, Los Angeles, USA.
Oncology Research Unit, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico.
BMJ Oncol. 2025 Apr 5;4(1):e000618. doi: 10.1136/bmjonc-2024-000618. eCollection 2025.
To demonstrate the significance of supercharged natural killer (sNK) cells to target aggressive gynecological tumours.
We used cell cultures of peripheral blood-derived mononuclear cells (PBMCs) and purified NK cells alone and in the presence of tumours. MHC-class gene expression assessments of ovarian tumours were performed using gene set enrichment analysis (GSEA). Secretion and expression levels of cytokines in PBMCs and NK cells were determined using ELISA and scRNA seq analysis, respectively. A flow cytometer was used for surface marker analysis. Cr and eSight were used to determine the killing activity of NK cells.
We have observed a significant decrease in the numbers and functions of NK cells in patients with ovarian cancer. GSEA revealed differently expressed genes, decreased differentiation- and immune-related genes, and increased genes for cell cycle analysis in recurrent tumours compared with chemo-naive ovarian tumours. Increased gene expression as well as secretion of interferon-γ and tumour necrosis factor-α and increased avidity in binding to tumour cells by sNK cells was observed. Unlike primary interleukin (IL)-2-activated NK cells, sNK cells effectively lysed OVCAR8 ovarian poorly differentiated cancer stem-like cells (PDCSCs) and well-differentiated OVCAR4 tumours. Primary ovarian tumours with lower MHC-class I expression were highly susceptible to both primary IL-2-activated NK and sNK cells, whereas the well-differentiated tumours with high expression of MHC-class I were only susceptible to sNK cells.
The use of sNK cells in immunotherapy emerges as a potentially effective strategy to target and eliminate the majority of ovarian tumour clones, thereby providing a potential therapeutic opportunity in preventing the recurrence of the disease.
证明超活化自然杀伤（sNK）细胞对侵袭性妇科肿瘤的靶向作用的重要性。
我们使用外周血来源的单核细胞（PBMC）和纯化的NK细胞进行细胞培养，分别单独培养以及在有肿瘤存在的情况下培养。使用基因集富集分析（GSEA）对卵巢肿瘤进行MHC-I类基因表达评估。分别使用酶联免疫吸附测定（ELISA）和单细胞RNA测序（scRNA seq）分析来测定PBMC和NK细胞中细胞因子的分泌和表达水平。使用流式细胞仪进行表面标志物分析。使用Cr和eSight来测定NK细胞的杀伤活性。
我们观察到卵巢癌患者的NK细胞数量和功能显著下降。GSEA显示，与未经化疗的卵巢肿瘤相比，复发性肿瘤中存在差异表达基因，分化和免疫相关基因减少，细胞周期分析相关基因增加。观察到sNK细胞的基因表达增加以及干扰素-γ和肿瘤坏死因子-α的分泌增加，并且与肿瘤细胞结合的亲和力增加。与原发性白细胞介素（IL）-2激活的NK细胞不同，sNK细胞能有效裂解OVCAR8卵巢低分化癌干细胞样细胞（PDCSC）和高分化的OVCAR4肿瘤。MHC-I类表达较低的原发性卵巢肿瘤对原发性IL-2激活的NK细胞和sNK细胞均高度敏感，而MHC-I类高表达的高分化肿瘤仅对sNK细胞敏感。
在免疫治疗中使用sNK细胞成为一种潜在有效的策略，可靶向并消除大多数卵巢肿瘤克隆，从而为预防疾病复发提供潜在的治疗机会。
