Sousa Luana Madalena, Almeida Jani-Sofia, Fortes-Andrade Tânia, Couceiro Patrícia, Rodrigues Joana, Fonseca Rúben, Santos-Rosa Manuel, Freitas-Tavares Paulo, Casanova José Manuel, Rodrigues-Santos Paulo
Laboratory of Immunology and Oncology, Center for Neuroscience and Cell Biology (CNC), University of Coimbra, 3004-504 Coimbra, Portugal.
Center for Innovation in Biomedicine and Biotechnology (CIBB), University of Coimbra, 3000-504 Coimbra, Portugal.
Cancers (Basel). 2025 Jul 30;17(15):2508. doi: 10.3390/cancers17152508.
Soft tissue sarcomas (STSs) are a rare and heterogeneous group of mesenchymal tumors with limited response to current therapies, particularly in advanced stages. STS tumors were traditionally considered "cold" tumors, characterized by limited immune infiltration and low immunogenicity. However, emerging evidence is challenging this perception, highlighting a potentially critical role for the immune system in STS biology.
Building on our previous findings suggesting impaired natural killer (NK) cell activity in STS patients, we aimed to perform an in-depth characterization of peripheral NK cells in STS.
Peripheral blood samples from STS patients and sex- and age-matched healthy donors were analyzed to assess NK cell degranulation, IFNγ production, and receptor repertoire.
Functional assays revealed a notable reduction in both degranulation and IFNγ production in NK cells from STS patients. STS patients also exhibited dysregulated expression of activating and inhibitory NK cell receptors. Principal component analysis (PCA) identified CD27 and NKp44 as critical markers for distinguishing STS patients from healthy donors. Increased CD27 expression represents a shift towards a more regulatory NK cell phenotype, and we found that CD27 expression was negatively correlated with NK cell degranulation and IFNγ production. ROC curve analysis demonstrated strong potential to distinguish between the groups for both CD27 (AUC = 0.85) and NKp44 (AUC = 0.94).
In conclusion, STS patients exhibited impaired NK cell function, altered receptor repertoire, and a shift towards a less cytotoxic and more regulatory phenotype.
软组织肉瘤（STS）是一组罕见的异质性间充质肿瘤，对当前治疗的反应有限，尤其是在晚期。传统上，STS肿瘤被认为是“冷”肿瘤，其特征是免疫浸润有限且免疫原性低。然而，新出现的证据正在挑战这一观念，突显了免疫系统在STS生物学中可能发挥的关键作用。
基于我们之前的研究结果表明STS患者自然杀伤（NK）细胞活性受损，我们旨在对STS患者外周血NK细胞进行深入表征。
分析STS患者以及性别和年龄匹配的健康供体的外周血样本，以评估NK细胞脱颗粒、IFNγ产生和受体库。
功能分析显示，STS患者NK细胞的脱颗粒和IFNγ产生均显著减少。STS患者还表现出激活和抑制性NK细胞受体的表达失调。主成分分析（PCA）确定CD27和NKp44是区分STS患者和健康供体的关键标志物。CD27表达增加代表向更具调节性的NK细胞表型转变，我们发现CD27表达与NK细胞脱颗粒和IFNγ产生呈负相关。ROC曲线分析表明，CD27（AUC = 0.85）和NKp44（AUC = 0.94）在区分两组方面具有很强的潜力。
总之，STS患者表现出NK细胞功能受损、受体库改变，以及向细胞毒性较小和调节性更强的表型转变。
