Identification and validation of poor prognosis immunoevasive subtype of esophageal cancer with tumor-infiltrating SAMD3 + NK cell abundance.

IF 5.1 2区医学 Q2 IMMUNOLOGY

Cancer Immunology, Immunotherapy Pub Date : 2025-04-19 DOI:10.1007/s00262-025-04028-w

Xu Huang, Runze You, Fangyi Liu, Zitao Jian, Guanyou Zhou, Hao Yin, Mengyuan Wu, Tiantao Sun, Zhiyun Duan, Wenyi Xu, Shaoyuan Zhang, Xinyu Yang, Heng Jiao, Shuyi Yang, Qingle Wang, Jun Yin, Han Tang, Miao Lin, Lijie Tan

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Abstract

Introduction: Esophageal cancer (EC) remains highly lethal due to tumor microenvironment (TME)-mediated immune evasion. While natural killer (NK) cells are central to antitumor immunity, their functional states in EC are poorly characterized.

Methods: We integrated bulk RNA-seq (TCGA/GEO) and single-cell data to construct an NK cell-derived prognostic signature (NK score) via LASSO-Cox regression. Immunofluorescence was applied to assess the clinical relevance of SAMD3 + NK cells in EC. Using both xenograft mouse models and in vitro co-culture procedures, the impact of SAMD3 on NK cell function was confirmed.

Results: In EC patients, the prognostic NK score-which is generated from important NK cell markers including SAMD3-was substantially correlated with a worse chance of survival. NK cells within the TME had significant levels of SAMD3 expression, as seen by immunofluorescence labeling. Moreover, NK cells with SAMD3 knockdown exhibited enhanced antitumor activity, leading to decreased tumor development in the xenograft model.

Discussion: Our results demonstrate the predictive significance of NK cell markers in EC and pinpoint SAMD3 as a critical modulator of NK cell activity. We pioneer SAMD3 + NK cells as architects of TME immunosuppression in EC. Our findings nominate SAMD3 inhibition as a combinatorial strategy to overcome immune checkpoint blockade resistance.

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肿瘤浸润SAMD3 + NK细胞丰度对食管癌不良预后免疫逃避亚型的鉴定与验证。

导读：食管癌（EC）由于肿瘤微环境（TME）介导的免疫逃避而具有高致死率。虽然自然杀伤（NK）细胞是抗肿瘤免疫的核心，但它们在EC中的功能状态却很少被表征。方法：我们整合了大量RNA-seq （TCGA/GEO）和单细胞数据，通过LASSO-Cox回归构建NK细胞衍生的预后特征（NK评分）。应用免疫荧光法评价SAMD3 + NK细胞在EC中的临床意义。通过异种移植小鼠模型和体外共培养程序，证实了SAMD3对NK细胞功能的影响。结果：在EC患者中，预后NK评分（由包括samd3在内的重要NK细胞标志物生成）与较差的生存机会显著相关。免疫荧光标记显示，TME内的NK细胞有显著水平的SAMD3表达。此外，SAMD3敲低的NK细胞表现出增强的抗肿瘤活性，导致异种移植模型中肿瘤发展减少。讨论：我们的研究结果证明了NK细胞标记物在EC中的预测意义，并指出SAMD3是NK细胞活性的关键调节剂。我们开创了SAMD3 + NK细胞作为EC中TME免疫抑制的建筑师。我们的研究结果表明SAMD3抑制是克服免疫检查点阻断抵抗的组合策略。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Immunology, Immunotherapy 医学-免疫学

CiteScore

10.50

自引率

1.70%

发文量

207

审稿时长

1 months

期刊介绍： Cancer Immunology, Immunotherapy has the basic aim of keeping readers informed of the latest research results in the fields of oncology and immunology. As knowledge expands, the scope of the journal has broadened to include more of the progress being made in the areas of biology concerned with biological response modifiers. This helps keep readers up to date on the latest advances in our understanding of tumor-host interactions. The journal publishes short editorials including "position papers," general reviews, original articles, and short communications, providing a forum for the most current experimental and clinical advances in tumor immunology.