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.

中文翻译：

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Egfl6 通过增强肿瘤相关髓细胞的免疫抑制功能促进卵巢癌进展


肿瘤相关巨噬细胞 （TAM） 和髓源性抑制细胞 （MDSC） 在免疫治疗耐药性中起关键作用。在这项研究中，我们确定了表皮生长因子样 6 （Egfl6） 是髓样细胞功能的调节因子。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，作为髓系细胞迁移的趋化因子，并促进它们分化为免疫抑制状态。在卵巢癌 （OvCa） 的同基因小鼠模型中，Egfl6 的肿瘤表达增加了多形核 （PMN） MDSCs 和 TAM 的瘤内积累及其免疫抑制因子（包括 CXCL2、IL-10 和 PD-L1）的表达。与此一致，在免疫“热”肿瘤模型中，Egfl6 表达消除了对抗 PD-L1 治疗的反应，而 Egfl6 中和抗体减少了肿瘤浸润 CD206⁺ TAM 和 PMN-MDSCs 的积累，并恢复了抗 PD-L1 治疗的疗效。支持在人肿瘤、人 OvCa 组织样本中发挥作用，EGFL6 高表达区域与骨髓细胞浸润共定位。scRNA-Seq 分析揭示了 EGFL6 与免疫抑制因子免疫细胞表达之间的相关性。我们的数据为 EGFL6 在介导肿瘤免疫抑制中的肿瘤免疫功能提供了机制见解，并确定 EGFL6 是增强 OvCa 患者免疫治疗的潜在治疗靶点。