Uptake of lipids from ascites drives NK cell metabolic dysfunction in ovarian cancer

IF 17.6 1区医学 Q1 IMMUNOLOGY

Science Immunology Pub Date : 2025-05-09 DOI:10.1126/sciimmunol.adr4795

Karen Slattery, Cong-Hui Yao, Eimear Mylod, John Scanlan, Barry Scott, Joseph Patrick Crowley, Orla McGowan, Gavin McManus, Martin Brennan, Katie O’Brien, Kate Glennon, Edward Corry, Ann Treacy, Rafael J. Argüello, Clair M. Gardiner, Marcia C. Haigis, Donal J. Brennan, Lydia Lynch

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Abstract

High-grade serous ovarian cancer (HGSOC) remains an urgent unmet clinical need, with more than 70% of patients presenting with metastatic disease. Many patients develop large volumes of ascites, which promotes metastasis and is associated with poor therapeutic response and survival. Immunotherapy trials have shown limited success, highlighting the need to better understand HGSOC immunology. Here, we analyzed cytotoxic lymphocytes [natural killer (NK), T, and innate T cells] from patients with HGSOC and observed widespread dysfunction across primary and metastatic sites. Although nutrient rich, ascites was immunosuppressive for all lymphocyte subsets. NK cell dysfunction was driven by uptake of polar lipids, with associated dysregulation in lipid storage. Phosphatidylcholine was a key immunosuppressive metabolite, disrupting NK cell membrane order and cytotoxicity. Blocking lipid uptake through SR-B1 protected NK cell antitumor functions in ascites. These findings offer insights into immune suppression in HGSOC and have important implications for the design of future immunotherapies.

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从腹水中摄取脂质驱动卵巢癌NK细胞代谢功能障碍

高级别浆液性卵巢癌（HGSOC）仍然是一个迫切的未满足的临床需求，超过70%的患者表现为转移性疾病。许多患者出现大量腹水，这促进了转移，并与较差的治疗反应和生存有关。免疫治疗试验显示有限的成功，强调需要更好地了解HGSOC免疫学。在这里，我们分析了HGSOC患者的细胞毒性淋巴细胞[自然杀伤（NK）， T细胞和先天T细胞]，并观察到原发和转移部位普遍存在功能障碍。虽然营养丰富，但腹水对所有淋巴细胞亚群都有免疫抑制作用。NK细胞功能障碍是由极性脂质的摄取驱动的，并伴有相关的脂质储存失调。磷脂酰胆碱是一个关键的免疫抑制代谢物，破坏NK细胞膜秩序和细胞毒性。通过SR-B1阻断脂质摄取保护腹水NK细胞抗肿瘤功能。这些发现为HGSOC的免疫抑制提供了见解，并对未来免疫疗法的设计具有重要意义。

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来源期刊

Science Immunology Immunology and Microbiology-Immunology

CiteScore

32.90

自引率

2.00%

发文量

183

期刊介绍： Science Immunology is a peer-reviewed journal that publishes original research articles in the field of immunology. The journal encourages the submission of research findings from all areas of immunology, including studies on innate and adaptive immunity, immune cell development and differentiation, immunogenomics, systems immunology, structural immunology, antigen presentation, immunometabolism, and mucosal immunology. Additionally, the journal covers research on immune contributions to health and disease, such as host defense, inflammation, cancer immunology, autoimmunity, allergy, transplantation, and immunodeficiency. Science Immunology maintains the same high-quality standard as other journals in the Science family and aims to facilitate understanding of the immune system by showcasing innovative advances in immunology research from all organisms and model systems, including humans.