Karlsson Veronika, Stål Ebba, Stoopendahl Emma, Ivarsson Anton, Leffler Hakon, Lycke Maria, Sundqvist Martina, Sundfeldt Karin, Christenson Karin, Bernson Elin
Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden.
Department of Oral Microbiology and Immunology, Institute of Odontology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Front Immunol. 2024 Dec 20;15:1506236. doi: 10.3389/fimmu.2024.1506236. eCollection 2024.
Ovarian cancer is a lethal disease with low survival rates for women diagnosed in advanced stages. Current cancer immunotherapies are not efficient in ovarian cancer, and there is therefore a significant need for novel treatment options. The β-galactoside-binding lectin, Galectin-3, is involved in different immune processes and has been associated with poor outcome in various cancer diagnoses. Here, we investigated how Galectin-3 affects the interaction between natural killer (NK) cells and neutrophils in the tumor microenvironment of ovarian cancer.
Ascites from the metastatic tumor microenvironment and cyst fluid from the primary tumor site were collected from patients with high-grade serous carcinoma (HGSC) together with peripheral blood samples. Galectin-3 concentration was measured in ascites, cyst fluid and serum or plasma. Neutrophils isolated from HGSC ascites and autologous blood were analyzed to evaluate priming status and production of reactive oxygen species. co-culture assays with NK cells, neutrophils and K562 target cells (cancer cell line) were conducted to evaluate NK cell viability, degranulation and cytotoxicity.
High levels of Galectin-3 were observed in cyst fluid and ascites from patients with HGSC. Neutrophils present in HGSC ascites showed signs of priming; however, the priming status varied greatly among the patient samples. Galectin-3 induced production of reactive oxygen species in ascites neutrophils, but only from a fraction of the patient samples, which is in line with the heterogenous priming status of the ascites neutrophils. In co-cultures with NK cells and K562 target cells, we observed that Galectin-3-induced production of reactive oxygen species in neutrophils resulted in decreased NK cell viability and lowered anti-tumor responses.
Taken together, our results demonstrate high levels of Galectin-3 in the tumormicroenvironment of HGSC. High levels of Galectin-3 may induce production of reactiveoxygen species in ascites neutrophils in some patients. In turn, reactive oxygen species produced by neutrophils may modulate the NK cell anti-tumor immunity. Together, this study suggests further investigation to evaluate if a Galectin-3-targeting therapy may be used in ovarian cancer.
卵巢癌是一种致命疾病，晚期确诊的女性生存率较低。目前的癌症免疫疗法对卵巢癌无效，因此迫切需要新的治疗方案。β-半乳糖苷结合凝集素半乳凝素-3参与不同的免疫过程，并且在各种癌症诊断中都与不良预后相关。在此，我们研究了半乳凝素-3如何影响卵巢癌肿瘤微环境中自然杀伤（NK）细胞与中性粒细胞之间的相互作用。
从高级别浆液性癌（HGSC）患者中收集转移瘤微环境的腹水和原发肿瘤部位的囊液以及外周血样本。测定腹水中、囊液以及血清或血浆中的半乳凝素-3浓度。分析从HGSC腹水中分离出的中性粒细胞和自体血中的中性粒细胞，以评估其预激状态和活性氧的产生。进行NK细胞、中性粒细胞与K562靶细胞（癌细胞系）的共培养试验，以评估NK细胞的活力、脱颗粒和细胞毒性。
在HGSC患者的囊液和腹水中观察到高水平的半乳凝素-3。HGSC腹水中的中性粒细胞显示出预激迹象；然而，患者样本之间的预激状态差异很大。半乳凝素-3诱导腹水中性粒细胞产生活性氧，但仅在一部分患者样本中如此，这与腹水中性粒细胞的异质性预激状态一致。在与NK细胞和K562靶细胞的共培养中，我们观察到半乳凝素-3诱导中性粒细胞产生活性氧导致NK细胞活力降低和抗肿瘤反应减弱。
综上所述，我们的结果表明HGSC肿瘤微环境中存在高水平的半乳凝素-3。高水平半乳凝素-3可能在一些患者中诱导腹水中性粒细胞产生活性氧。反过来，中性粒细胞产生的活性氧可能调节NK细胞的抗肿瘤免疫。总之，本研究建议进一步研究以评估靶向半乳凝素-3的疗法是否可用于卵巢癌。
