The impact of Charcot-Leyden Crystal protein on mesothelioma chemotherapy: targeting eosinophils for enhanced chemosensitivity.

IF 9.7 1区医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

EBioMedicine Pub Date : 2024-10-28 DOI:10.1016/j.ebiom.2024.105418

Mégane Willems, Malik Hamaidia, Alexis Fontaine, Mélanie Grégoire, Louise Halkin, Lea Vilanova Mañá, Roxane Terres, Majeed Jamakhani, Sophie Deshayes, Yves Brostaux, Vincent Heinen, Renaud Louis, Bernard Duysinx, Didier Jean, Eric Wasielewski, Arnaud Scherpereel, Christophe Blanquart, Luc Willems

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引用次数: 0

Abstract

Background: In mesothelioma (MPM), clinical evidence indicates that the absolute eosinophil count negatively correlates with overall survival and response to standard chemotherapy. Since eosinophils poorly infiltrate MPM tumours, we hypothesised that endocrine rather than paracrine pathways mediate the therapeutic response. We thus studied the effect of eosinophil-associated factors on response to chemotherapy in mesothelioma.

Methods: The culture supernatant conditioned by primary human eosinophils was added to mesothelioma cells in presence of the standard chemotherapeutic regimen. The effectiveness of an anti-eosinophil treatment was evaluated in a preclinical model of C57BL/6 mice transplanted with mesothelioma tumour cells.

Findings: Supernatant of eosinophils differentiated from EOL1 cells or directly isolated from peripheral blood inhibited apoptosis induced by cisplatin and pemetrexed in 2D cultures and in spheroids. Transcriptomic analysis indicated that the anti-apoptotic effect mediated by eosinophils involved molecular interactions with the Charcot-Leyden Crystal protein or Galectin-10 (CLC-P/Gal10). The functional relevance of CLC-P/Gal10 was demonstrated by antibody-mediated depletion. Recombinant human CLC-P/Gal10 mimicked the anti-apoptotic activity of eosinophil-derived supernatants. In the mouse model, eosinophilia did not significantly affect tumour growth but altered the response to chemotherapy. Finally, pretreatment of eosinophilia with the anti-Siglec-F antibody before chemotherapy restored the effectiveness of the treatment.

Interpretation: This study provides a mechanistic rationale to clinical evidence correlating the poor outcome of patients with mesothelioma and with eosinophil-derived CLC-P/Gal10, opening new prospects for intervention in this fatal solid tumour.

Funding: Belgian Foundation against Cancer, Fonds National de la Recherche Scientifique (FNRS), Télévie, Foundation Léon Fredericq, ULiège.

查看原文本刊更多论文

Charcot-Leyden 晶体蛋白对间皮瘤化疗的影响：针对嗜酸性粒细胞增强化疗敏感性。

背景：临床证据表明，在间皮瘤（MPM）中，嗜酸性粒细胞绝对数与总生存率和对标准化疗的反应呈负相关。由于嗜酸性粒细胞很少浸润间皮瘤肿瘤，我们假设是内分泌途径而不是旁分泌途径介导了治疗反应。因此，我们研究了嗜酸性粒细胞相关因子对间皮瘤化疗反应的影响：方法：将原代人嗜酸性粒细胞条件培养上清液加入间皮瘤细胞，同时使用标准化疗方案。在移植了间皮瘤肿瘤细胞的 C57BL/6 小鼠临床前模型中评估了抗嗜酸性粒细胞治疗的有效性：从 EOL1 细胞分化出的嗜酸性粒细胞上清液或直接从外周血中分离出的嗜酸性粒细胞上清液抑制了顺铂和培美曲塞在二维培养物和球形培养物中诱导的细胞凋亡。转录组分析表明，嗜酸性粒细胞介导的抗凋亡效应涉及与夏科-莱登晶体蛋白或Galectin-10（CLC-P/Gal10）的分子相互作用。抗体介导的耗竭证明了 CLC-P/Gal10 的功能相关性。重组人 CLC-P/Gal10 模拟了嗜酸性粒细胞上清液的抗凋亡活性。在小鼠模型中，嗜酸性粒细胞增多并不会明显影响肿瘤的生长，但会改变对化疗的反应。最后，在化疗前用抗Siglec-F抗体对嗜酸性粒细胞进行预处理可恢复治疗效果：这项研究为间皮瘤患者的不良预后与嗜酸性粒细胞衍生的CLC-P/Gal10相关的临床证据提供了机理依据，为干预这种致命的实体瘤开辟了新的前景：比利时抗癌基金会、国家科学研究基金会（FNRS）、Télévie、Léon Fredericq 基金会、ULiège。

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

EBioMedicine Biochemistry, Genetics and Molecular Biology-General Biochemistry,Genetics and Molecular Biology

CiteScore

17.70

自引率

0.90%

发文量

579

审稿时长

5 weeks

期刊介绍： eBioMedicine is a comprehensive biomedical research journal that covers a wide range of studies that are relevant to human health. Our focus is on original research that explores the fundamental factors influencing human health and disease, including the discovery of new therapeutic targets and treatments, the identification of biomarkers and diagnostic tools, and the investigation and modification of disease pathways and mechanisms. We welcome studies from any biomedical discipline that contribute to our understanding of disease and aim to improve human health.