Molecular and Cellular Epigenetics (GIGA) and Molecular Biology (TERRA), University of Liege, Liege & Gembloux, Belgium.
Institut National de la Santé et de la Recherche Médicale (INSERM) U1232 Centre de Recherche en Cancérologie et Immunologie Nantes Angers (CRCINA), Nantes, France.
EBioMedicine. 2024 Nov;109:105418. doi: 10.1016/j.ebiom.2024.105418. Epub 2024 Oct 30.
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.
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.
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.
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.
Belgian Foundation against Cancer, Fonds National de la Recherche Scientifique (FNRS), Télévie, Foundation Léon Fredericq, ULiège.
在间皮瘤（MPM）中，临床证据表明绝对嗜酸性粒细胞计数与总生存期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 MPM 肿瘤，我们假设内分泌途径而不是旁分泌途径介导治疗反应。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。
将原代人嗜酸性粒细胞的培养上清液加入到存在标准化疗方案的间皮瘤细胞中。在 C57BL/6 小鼠移植间皮瘤肿瘤细胞的临床前模型中评估抗嗜酸性粒细胞治疗的效果。
EOL1 细胞分化的嗜酸性粒细胞或直接从外周血中分离的上清液抑制了 2D 培养物和球体中顺铂和培美曲塞诱导的细胞凋亡。转录组分析表明，嗜酸性粒细胞介导的抗凋亡作用涉及与 Charcot-Leyden Crystal 蛋白或半乳糖凝集素-10（CLC-P/Gal10）的分子相互作用。CLC-P/Gal10 的功能相关性通过抗体介导的耗竭得到证实。重组人 CLC-P/Gal10 模拟了嗜酸性粒细胞衍生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显著影响肿瘤生长，但改变了对化疗的反应。最后，在化疗前用抗 Siglec-F 抗体预处理嗜酸性粒细胞恢复了治疗的有效性。
这项研究为临床证据提供了一种机制基础，该证据将间皮瘤患者和嗜酸性粒细胞衍生的 CLC-P/Gal10 预后不良相关联，为干预这种致命的实体瘤开辟了新的前景。
比利时癌症基金会、比利时国家科学研究基金会（FNRS）、Télévie、Léon Fredericq 基金会、列日大学。
