Regulation of transendothelial migration of Tregs in irradiated HNSCCs by EphB4-ephrinB2 interaction

EphB4-ephrinB2 相互作用对受辐射 HNSCC 中 Tregs 跨内皮迁移的调节

基本信息

  • 批准号:
    10415869
  • 负责人:
  • 金额:
    $ 4.36万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-07-01 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

Abstract Resistance to radiation therapy (RT) remains a challenging problem for high-risk head and neck squamous cell carcinoma (HNSCC) patients. Anti-PD1 is now approved in the first- and second-line settings, indicating that the majority of these tumors are resistant to treatment. The field awaits the results of multiple trials testing whether combining immunotherapy and RT can help avoid resistance to RT, but many preclinical studies (including those from our lab) indicate that treatment resistance still develops despite such combinations. The preferential recruitment of unique immunosuppressive cell subtypes after RT to the tumor microenvironment (TME) in response to RT plays an important role in contributing to the promotion of tumor growth and progression. The tumor endothelium can act as a selective barrier that regulates the entry, stability, and activation status of immune cells, but the mechanistic underpinnings of this barrier activity remain poorly understood. The EphB4 receptor tyrosine kinase and its ligand ephrinB2 define novel molecular targets. Upon cell to cell contact, both EphB4 and ephrinB2 can signal via their cytoplasmic domains. Though they have been extensively studied in cell migration and angiogenesis in early embryonic development, little has been published on their role in modulating the cancer immune microenvironment. Our data show that ephrinB2 is expressed on the tumor vasculature and is upregulated by RT and that EphB4 is expressed on immunosuppressive regulatory T cells (Tregs). Inhibiting EphB4-ephrinB2 interaction with a peptide (TNYL-RAW) results in the selective, and exclusive, reduction in infiltration of Tregs while increasing activation of CD8+ and CD4+Foxp3- T cell populations. Tregs, we have demonstrated, play a key role in the development of resistance to RT, and their depletion re-establishes responsiveness to therapy in HNSCC murine models. We hypothesize that RT’s upregulation of ephrinB2 on tumor endothelial cells acts preferentially on EphB4 expressing Tregs, and blocking this interaction reduces their intratumoral infiltration and survival, which allows CD8+ and CD4+ effector cells to induce tumor regression. In Aim 1, we will analyze the mechanistic outcomes of Treg EphB4 and endothelial ephrinB2 interaction on Treg transendothelial trafficking, intratumoral homing, and survival using genetically engineered animal models with ephrinB2 deleted on endothelial cells or EphB4 deletion on Tregs after RT. In Aim 2, we will interrogate the cellular and molecular mechanisms triggered by the interaction between endothelial ephrinB2 and EphB4- expressing Tregs in endothelial-Treg co-culture assays after RT. Targeted inhibition of STAT3, AKT, Erk pathways will be done with pharmacological inhibitors based on our preliminary data. We expect that these studies will elucidate the molecular and cellular parameters of EphB4-ephrinB2 inhibitors and will provide the necessary information to develop a more effective therapy for RT resistant HNSCC.
摘要 头颈部鳞状细胞癌的放射治疗抵抗是一个具有挑战性的问题 癌(HNSCC)患者。抗PD 1现已获准用于一线和二线治疗,这表明 这些肿瘤中的大多数对治疗有抗性。该领域正在等待多项试验的结果, 结合免疫疗法和RT可以帮助避免对RT的耐药性,但许多临床前研究(包括那些 来自我们实验室)表明,尽管有这样的组合,治疗抗性仍然会发展。优惠 RT后将独特的免疫抑制细胞亚型招募到肿瘤微环境(TME)中 对RT的应答在促进肿瘤生长和进展中起重要作用。的 肿瘤内皮细胞可以作为一种选择性屏障,调节肿瘤细胞的进入、稳定性和激活状态。 免疫细胞,但这种屏障活性的机制基础仍然知之甚少。EphB4 受体酪氨酸激酶及其配体ephrinB 2定义了新的分子靶点。当细胞与细胞接触时, EphB 4和ephrinB 2可以通过它们的胞质结构域进行信号传导。尽管它们在1997年被广泛研究, 细胞迁移和血管生成在早期胚胎发育中的作用,很少有关于它们在 调节癌症免疫微环境。我们的数据显示ephrinB 2在肿瘤上表达, EphB 4在免疫抑制调节性T细胞上表达, (Tennis).抑制EphB 4-肝配蛋白B2与肽(TNYL-RAW)的相互作用导致选择性的,排他性的, 减少T细胞浸润,同时增加CD 8+和CD 4 + Foxp 3- T细胞群的活化。塔奇, 我们已经证明,在RT耐药性的发展中起着关键作用,它们的消耗重新建立了 在HNSCC鼠模型中对治疗的反应性。我们假设RT上调ephrinB 2, 肿瘤内皮细胞优先作用于EphB 4表达的TcR,阻断这种相互作用可降低其表达。 肿瘤内浸润和存活,这允许CD 8+和CD 4+效应细胞诱导肿瘤消退。在 目的1,我们将分析Treg EphB 4和内皮ephrinB 2相互作用对Treg 使用基因工程动物模型, 在目的2中,我们将询问在RT后内皮细胞上EphrinB 2缺失或TCFs上EphB 4缺失。 由内皮ephrinB 2和EphB 4之间的相互作用触发的细胞和分子机制- 在RT后的内皮-Treg共培养测定中表达TcR。 基于我们的初步数据,将使用药理学抑制剂来研究这些途径。我们预计这些 研究将阐明EphB 4-ephrinB 2抑制剂的分子和细胞参数,并将提供 这是开发RT耐药HNSCC更有效疗法的必要信息。

项目成果

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Laurel B Darragh其他文献

Laurel B Darragh的其他文献

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{{ truncateString('Laurel B Darragh', 18)}}的其他基金

Regulation of transendothelial migration of Tregs in irradiated HNSCCs by EphB4-ephrinB2 interaction
EphB4-ephrinB2 相互作用对受辐射 HNSCC 中 Tregs 跨内皮迁移的调节
  • 批准号:
    10643984
  • 财政年份:
    2021
  • 资助金额:
    $ 4.36万
  • 项目类别:
Regulation of transendothelial migration of Tregs in irradiated HNSCCs by EphB4-ephrinB2 interaction
EphB4-ephrinB2 相互作用对受辐射 HNSCC 中 Tregs 跨内皮迁移的调节
  • 批准号:
    10315419
  • 财政年份:
    2021
  • 资助金额:
    $ 4.36万
  • 项目类别:

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