肿瘤细胞治疗研究
英文原题：TP53 Loss Elevates NF-κB-IFN-β-MHC-Ia Signaling to Promote NK Cell Resistance in Osteosarcoma.
TP53 Loss Elevates NF-κB-IFN-β-MHC-Ia Signaling to Promote NK Cell Resistance in Osteosarcoma.
TP53失活是骨肉瘤（OS）发生中的关键事件，也是其侵袭性的基础，但其在肿瘤-免疫相互作用中的作用仍知之甚少。
TP53失活是骨肉瘤（OS）发生中的关键事件，也是其侵袭性的基础，但其在肿瘤-免疫相互作用中的作用仍知之甚少。在此，我们利用OS细胞系和干细胞来源的OS相关模型，研究p53缺失如何改变骨肉瘤对自然杀伤（NK）细胞介导的细胞毒作用的易感性。我们发现，人骨肉瘤细胞系中TP53缺失导致NK细胞调节配体失调，特别是上调MHC-Ia以赋予对NK细胞杀伤的抵抗。临床标本的单细胞RNA测序显示，间充质干细胞（MSCs）与OS发生相关。利用人胚胎干细胞（hESC）来源的MSCs，该研究表明TP53缺失还通过激活胞质dsDNA-NF-κB-IFN-β轴驱动MHC-Ia过表达和NK细胞抵抗。同基因小鼠模型证实，与野生型对照相比，p53缺失导致更具侵袭性的肿瘤，且NK细胞浸润减少。在临床上，p53功能受损与MHC-Ia表达升高和I型IFN信号传导相关。这些发现揭示，TP53缺失触发的NF-κB-IFN-β-MHC-Ia轴促进OS发生中的NK细胞抵抗，并凸显其作为早期干预关键治疗靶点的潜力。
TP53 inactivation is a key event in osteosarcoma (OS) development and underlies its aggressiveness, yet its role in tumor-immune interactions remains poorly understood. Here, we investigate how p53 loss alters osteosarcoma susceptibility to natural killer (NK) cell-mediated cytotoxicity using OS cell lines and stem cell-derived OS-associated models. We found that TP53 loss in human osteosarcoma cell lines dysregulates NK cell regulatory ligands, specifically upregulating MHC-Ia to confer resistance to NK cell killing. Single-cell RNA sequencing of clinical specimens reveals mesenchymal stem cells (MSCs) is associated with OS development. Using human embryonic stem cell (hESC)-derived MSCs, the study shows that TP53 loss also drives MHC-Ia overexpression and NK cell resistance via activation of the cytosolic dsDNA-NF-κB-IFN-β axis. Syngeneic mouse models confirmed that p53 loss results in more aggressive tumors with reduced NK cell infiltration than wild-type controls. Clinically, impaired p53 function correlates with elevated MHC-Ia expression and type I IFN signaling. These findings uncover that a TP53 loss-triggered NF-κB-IFN-β-MHC-Ia axis contributes to NK cell resistance in OS development and highlight its potential as a critical therapeutic target for early intervention.
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