Inhibition of EphB4-Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers
Inhibition of EphB4-Ephrin-B2 Signaling Reprograms the Tumor Immune Microenvironment in Head and Neck Cancers
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DOI：
10.1158/0008-5472.can-18-3257
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发表时间：
2019-05-15
期刊：
影响因子：
11.2
通讯作者：
Karam, Sana D.
中科院分区：
文献类型：
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作者：
Bhatia, Shilpa;Oweida, Ayman;Karam, Sana D.
识别肿瘤微环境中有助于免疫逃避的靶点已成为一个重要的研究领域。在这项研究中，我们发现EphB4-eparin-B2信号是免疫系统固有和适应性成分的调节因子。EphB4属于受体酪氨酸激酶家族，在细胞-细胞接触部位与ePhin-B2配体相互作用，产生双向信号转导。我们发现，与对照组相比，在原位头颈部鳞状细胞癌(HNSCC)模型中，单独或与放射(RT)联合抑制EphB4-ePhin-B2减少了瘤内调节性T细胞(Tregs)，增加了CD8(+)和CD4(+)Foxp3(-)T细胞的激活。我们还比较了EphB4-ePhin-B2联合RT和联合抗PDL1和RT的效果，观察到相似的肿瘤生长抑制，特别是在早期时间点。患者来源的异种移植模型显示肿瘤相关的M2巨噬细胞减少，并在用RT抑制EphB4-ephin-B2后偏向抗肿瘤的M1表型。在体外，与对照组相比，EphB4信号抑制降低了Ki67表达的Tregs和Treg的激活。总体而言，我们的研究是第一次发现EphB4-eparin-B2在肿瘤免疫反应中的作用。此外，我们的研究结果表明，EphB4-ePhrin-B2抑制联合RT是HNSCC患者的一种潜在的替代方案，对于不符合或不能耐受抗PDL1治疗的患者可能特别有益。意义：这些发现提出了EphB4-ePhrin-B2抑制作为抗PDL1治疗的替代方案，可以与放射联合使用，在HNSCC患者中诱导有效的抗肿瘤免疫反应。
Identifying targets present in the tumor microenvironment that contribute to immune evasion has become an important area of research. In this study, we identified EphB4-ephrin-B2 signaling as a regulator of both innate and adaptive components of the immune system. EphB4 belongs to receptor tyrosine kinase family that interacts with ephrin-B2 ligand at sites of cell-cell contact, resulting in bidirectional signaling. We found that EphB4-ephrin-B2 inhibition alone or in combination with radiation (RT) reduced intratumoral regulatory T cells (Tregs) and increased activation of both CD8(+) and CD4(+) Foxp3(-) T cells compared with the control group in an orthotopic head and neck squamous cell carcinoma (HNSCC) model. We also compared the effect of EphB4-ephrin-B2 inhibition combined with RT with combined anti-PDL1 and RT and observed similar tumor growth suppression, particularly at early time-points. A patient-derived xenograft model showed reduction of tumor-associated M2 macrophages and favored polarization towards an antitumoral M1 phenotype following EphB4-ephrin-B2 inhibition with RT. In vitro, EphB4 signaling inhibition decreased Ki67-expressing Tregs and Treg activation compared with the control group. Overall, our study is the first to implicate the role of EphB4-ephrin-B2 in tumor immune response. Moreover, our findings suggest that EphB4-ephrin-B2 inhibition combined with RT represents a potential alternative for patients with HNSCC and could be particularly beneficial for patients who are ineligible to receive or cannot tolerate anti-PDL1 therapy.Significance: These findings present EphB4-ephrin-B2 inhibition as an alternative to anti-PDL1 therapeutics that can be used in combination with radiation to induce an effective antitumor immune response in patients with HNSCC.