肿瘤细胞治疗研究
英文原题：ZNF683(+) NK cells govern chemotherapy sensitivity in advanced HPSCC via reshaping immune microenvironment.
下咽鳞状细胞癌（HPSCC）是一种侵袭性强、预后极差的头颈部恶性肿瘤，对标准化疗方案TPF（多西他赛、顺铂、5-氟尿嘧啶）存在持续性耐药。
下咽鳞状细胞癌（HPSCC）是一种侵袭性头颈癌，预后极差，对标准化疗方案TPF（多西他赛、顺铂、5-氟尿嘧啶）持续存在化疗耐药。然而，化疗耐药背后的免疫学机制仍未明确。在此，我们对配对的TPF治疗前/后HPSCC标本进行了纵向单细胞RNA测序（scRNA-seq）分析，绘制了化疗耐药背后的免疫细胞动态图谱。我们的研究通过整合单细胞转录组学、空间多重免疫组化和功能验证，鉴定出ZNF683+自然杀伤（NK）细胞是化疗疗效的守门人。此外，治疗前基线ZNF683+NK细胞富集可预测TPF应答，而GZMK+CD8+效应记忆T细胞是TPF成功干预的主要免疫效应细胞。在机制上，生物信息学和体外共培养数据揭示，ZNF683+NK细胞直接与CD8+T细胞相互作用，并驱动MHC-I依赖性的多功能GZMK+CD8+效应记忆T细胞许可。总体而言，这一NK-CD8+轴为克服HPSCC患者化疗耐药提供了潜在的预测生物标志物和治疗靶点。
Hypopharyngeal squamous cell carcinoma (HPSCC), an aggressive head and neck cancer with dismal prognosis, faces persistent chemoresistance to standard TPF (docetaxel, cisplatin, 5-fluorouracil) regimen. However, the immunological mechanisms underlying chemoresistance remain undefined. Here, we perform longitudinal single-cell RNA sequencing (scRNA-seq) profiling of paired pre-/post-TPF HPSCC specimens, mapping immune cell dynamics underlying chemoresistance. Our study identifies ZNF683 + natural killer (NK) cells as a gatekeeper of chemotherapy efficacy through integrated single-cell transcriptomics, spatial multiplex immunohistochemistry and functional validation. Moreover, pretreatment baseline enrichment of ZNF683 + NK cells predicts TPF response, while GZMK + CD8 + effector memory T cells function as the predominant immunologic effector to successful TPF intervention. Mechanistically, bioinformatics and in vitro coculture data reveal that ZNF683 + NK cells directly interact with CD8 + T cells, and drive an MHC-I-dependent licensing of polyfunctional GZMK + CD8 + effector memory T cells. Collectively, this NK-CD8 + axis provides a potential predictive biomarker and therapeutic target to overcome chemoresistance in patients with HPSCC.
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