Targeting EphB4-ephrinB2 to decrease immunosuppression in HNSCC

靶向 EphB4-ephrinB2 减少 HNSCC 的免疫抑制

基本信息

批准号：
10268845
负责人：
SANA KARAM
金额：
$ 34.95万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10268845
关键词：
Adhesions Affect Autoimmune Beds Biological Assay Blood Vessels Blood specimen Cell Communication Cell Proliferation Cell Survival Cell physiology Cells Clinical Trials Coculture Techniques Colorado Cytometry Cytoplasmic Tail Data Diagnostic radiologic examination Disease Embryonic Development Endothelial Cells Endothelium Enrollment Environment EphB4 Receptor Ephrin-B2 Flow Cytometry Genetic Genetically Engineered Mouse Goals Head and Neck Cancer Head and Neck Squamous Cell Carcinoma Human Image Immune Immune Evasion Immune Targeting Immune checkpoint inhibitor Immunocompetent Immunofluorescence Immunologic Immunofluorescence Microscopy Immunologics Immunosuppression Immunotherapeutic agent Implant In Vitro Infiltration Intervention L-Selectin Ligands Macrophage Activation Malignant Neoplasms Mediating Mediator of activation protein Methods Molecular Molecular Target Outcome Participant Pathway interactions Patients Pharmaceutical Preparations Pharmacology Phase I/II Trial Phenotype Play Population Pre-Clinical Model Process Proto-Oncogene Proteins c-akt Publishing Radiation Radiation therapy Receptor Protein-Tyrosine Kinases Regulatory T-Lymphocyte Research Resistance Role STAT3 gene Sampling Signal Transduction Smoking History Specimen Stress Fibers System T cell response Target Populations Testing Tissues Tumor Promotion Tumor-associated macrophages Tumor-infiltrating immune cells Vascular Endothelial Cell angiogenesis anti-tumor immune response base cancer cell cell motility chemoradiation cytokine effector T cell head and neck cancer patient high risk immunological status immunotherapy trials in vivo inhibitor/antagonist intravital microscopy knock-down macrophage migration monocyte neoplastic cell novel potential biomarker pre-clinical predictive marker radiation response receptor recruit response response biomarker side effect therapeutic target therapy resistant trafficking transcriptome sequencing tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions

项目摘要

SUMMARY, Project 1 Treatment resistance remains a challenging problem for high-risk head and neck cancer (HNSCC) patients. Current trials with immune checkpoint inhibitors have yielded sub-optimal response rates. This could be due to TME factors that substantially modulate the immune landscape’s composition, phenotype, and function. Preferential recruitment of unique immunosuppressive cell subtypes to the tumor bed may play an important role in contributing to the promotion of tumor growth and progression. The tumor endothelium can act as a selective barrier that regulates entry, stability, and activation status of immune cells, but the mechanistic underpinnings remain poorly understood. The EphB4 receptor tyrosine kinase and its ligand EFNB2 define novel molecular targets. Although they have been studied in cell migration and angiogenesis in early embryonic development, little has been published on their role in modulating the cancer immune microenvironment. Our preliminary data show that HNSCCs are enriched in regulatory T-cells (Tregs) and tumor associated macrophages (TAMs), both of which contribute to resistance after RT. EFNB2 is upregulated on tumor vasculature after RT whereas EphB4 is expressed on Tregs and TAMs, and among all immune cells, Tregs and TAMs are most sensitive to either pharmacologic inhibition with TNYL-RAW or genetic knockdown of endothelial EFNB2 in the context of RT. We therefore hypothesize that RT upregulates EFNB2 on tumor vascular endothelial cells, which acts preferentially to recruit EphB4 expressing Tregs and TAMs. Blockade of EphB4-EFNB2 signaling at the tumor endothelial barrier will hinder Tregs’ and TAMs’ ability to infiltrate and promote cancer cell survival or suppress Teff function. In Aim1, we will analyze the mechanistic outcome of the interaction between immune cell EphB4 and endothelial EFNB2 on immune trans-endothelial trafficking, survival, polarization, and differentiation of immune cells as well as vascular normalization of endothelial cells in response to RT. We will use pharmacological inhibitors as well as GEMMs with EFNB2 deletion on endothelial cells or EphB4 deletion on Tregs or TAMs. Aim 2 will study the cellular and molecular mechanisms triggered by the interaction between endothelial EFNB2 and EphB4-expressing immune cells on immune cell processes in response to RT using endothelial-immune cells co-culture assays. Targeted inhibition of STAT3, AKT, and Erk pathway will be done with pharmacological inhibitors based on our preliminary data. Aim 3 will use tissue from a human clinical trial with sEphB4-HSA (an inhibitor currently in Phase I and II trials) before and after drug alone or drug and chemoradiation alone. This will serve to identify the molecular mediators that drive the anti-tumor immune response to this therapy. These studies will also collectively elucidate the molecular and cellular parameters of EphB4-EFNB2 inhibitors and will allow for the identification of potential predictive markers for this using EphB4- EFNB2 inhibitors.

摘要，项目1 对于高风险的头颈癌（HNSCC）患者，治疗耐药性仍然是一个挑战问题。当前具有免疫切克点抑制剂的试验产生了亚最佳反应率。这可能是由于 TME因素基本上调节了免疫景观的组成，表型和功能。优先募集独特的免疫抑制细胞亚型为肿瘤床可能起重要作用在促进肿瘤生长和进展的过程中。肿瘤内皮可以作为选择性调节免疫细胞的进入，稳定性和激活状态的障碍，但机械基础保持不当理解。 EPHB4受体酪氨酸激酶及其配体EFNB2定义了新的分子目标。尽管它们已经在早期胚胎发育中研究了细胞迁移和血管生成，但关于它们在调节癌症免疫微环境中的作用几乎没有发表。我们的初步数据表明HNSCC在调节性T细胞（TREG）和肿瘤相关巨噬细胞（TAM）中富含其中有助于RT后阻力。 EFNB2在RT之后进行了肿瘤脉管系统的更新，而EPHB4已更新在Treg和TAM上表达，在所有免疫细胞中，Tregs和TAM在在RT的背景下，用TNYL-RAW或内皮EFNB2的遗传敲低的药理学抑制作用。我们因此，假设RT在肿瘤血管内皮细胞上上调EFNB2，该细胞起作用优先募集EPHB4表达Treg和TAM。封锁EPHB4-EFNB2信号在肿瘤内皮屏障将阻碍Tregs和TAM浸润和促进癌细胞存活的能力或抑制TEFF功能。在AIM1中，我们将分析免疫之间相互作用的机械结果细胞EPHB4和内皮EFNB2在免疫跨内皮贩运，生存，极化和免疫细胞的分化以及响应RT的内皮细胞的血管归一化。我们将在内皮细胞或EPHB4缺失上使用药物抑制剂以及具有EFNB2缺失的GEMM 在Tregs或Tams上。 AIM 2将研究由相互作用触发的细胞和分子机制内皮EFNB2和EPHB4表达免疫球的免疫球体，以响应RT使用内皮免疫细胞共培养分析。将完成针对STAT3，AKT和ERK途径的目标抑制基于我们的初步数据，使用药物抑制剂。 AIM 3将使用人类临床试验的组织单独药物或药物之前和之后，使用SEPHB4-HSA（目前正在I阶段和II期试验中的抑制剂）以及单独化学放疗。这将有助于识别驱动抗肿瘤免疫的分子介质对这种疗法的反应。这些研究还将集体阐明分子和细胞参数 EPHB4-EFNB2抑制剂，将允许使用EPHB4-鉴定潜在的预测标志物 EFNB2抑制剂。