Egfl6 promotes ovarian cancer progression by enhancing the immunosuppressive functions of tumor-associated myeloid cells.

IF 13.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL
Sarah Hamze Sinno, Joshua A Imperatore, Shoumei Bai, Noémie Gomes-Jourdan, Nyasha Mafarachisi, Claudia Coronnello, Linan Zhang, Eldin Jašarević, Hatice U Osmanbeyoglu, Ronald J Buckanovich, Sandra Cascio
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Abstract

Tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) play a critical role in resistance to immunotherapy. In this study, we identified epidermal growth factor-like 6 (Egfl6) as a regulator of myeloid cell functions. Our analyses indicated that Egfl6, via binding with β3 integrins and activation of p38 and SYK signaling, acts as a chemotactic factor for myeloid cell migration and promotes their differentiation toward an immunosuppressive state. In syngeneic mouse models of ovarian cancer (OvCa), tumor expression of Egfl6 increased the intratumoral accumulation of polymorphonuclear (PMN) MDSCs and TAMs and their expression of immunosuppressive factors, including CXCL2, IL-10, and PD-L1. Consistent with this, in an immune 'hot' tumor model, Egfl6 expression eliminated response to anti-PD-L1 therapy, while Egfl6 neutralizing antibody decreased the accumulation of tumor-infiltrating CD206+ TAMs and PMN-MDSCs and restored the efficacy of anti-PD-L1 therapy. Supporting a role in human tumors, in human OvCa tissue samples, areas of high EGFL6 expression colocalized with myeloid cell infiltration. scRNA-Seq analyses revealed a correlation between EGFL6 and immune cell expression of immunosuppressive factors. Our data provide mechanistic insights into the oncoimmunologic functions of EGFL6 in mediating tumor immune suppression and identified EGFL6 as a potential therapeutic target to enhance immunotherapy in patients with OvCa.

Egfl6 通过增强肿瘤相关髓系细胞的免疫抑制功能来促进卵巢癌的进展。
肿瘤相关巨噬细胞(TAMs)和髓源抑制细胞(MDSCs)在免疫疗法的抗药性中起着至关重要的作用。在这项研究中,我们发现表皮生长因子样 6(Egfl6)是髓样细胞功能的新调节因子。我们的分析表明,Egfl6通过与β3整合素结合并激活p38和SYK信号传导,可作为髓系细胞迁移的趋化因子,并促进髓系细胞向免疫抑制状态分化。在卵巢癌(OvCa)的合成小鼠模型中,肿瘤表达 Egfl6 会增加多形核(PMN)MDSCs 和 TAMs 在肿瘤内的聚集,并增加它们对免疫抑制因子(包括 CXCL2、IL-10 和 PD-L1)的表达。与此相一致的是,在免疫 "热 "肿瘤模型中,Egfl6的表达消除了对a-PD-L1疗法的反应,而Egfl6中和抗体减少了肿瘤浸润CD206+ TAMs和PMN-MDSCs的积累,恢复了a-PD-L1疗法的疗效。scRNAseq分析表明,EGFL6与免疫细胞表达免疫抑制因子之间存在相关性。我们的数据从机理上揭示了 EGFL6 在介导肿瘤免疫抑制方面的协同免疫功能,并将 EGFL6 鉴定为一种潜在的新型治疗靶点,以增强卵巢癌患者的免疫疗法。
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
Journal of Clinical Investigation
Journal of Clinical Investigation 医学-医学:研究与实验
CiteScore
24.50
自引率
1.30%
发文量
1034
审稿时长
2 months
期刊介绍: The Journal of Clinical Investigation, established in 1924 by the ASCI, is a prestigious publication that focuses on breakthroughs in basic and clinical biomedical science, with the goal of advancing the field of medicine. With an impressive Impact Factor of 15.9 in 2022, it is recognized as one of the leading journals in the "Medicine, Research & Experimental" category of the Web of Science. The journal attracts a diverse readership from various medical disciplines and sectors. It publishes a wide range of research articles encompassing all biomedical specialties, including Autoimmunity, Gastroenterology, Immunology, Metabolism, Nephrology, Neuroscience, Oncology, Pulmonology, Vascular Biology, and many others. The Editorial Board consists of esteemed academic editors who possess extensive expertise in their respective fields. They are actively involved in research, ensuring the journal's high standards of publication and scientific rigor.
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