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：
10704596
负责人：
SANA KARAM
金额：
$ 32.47万
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/10704596
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 Cytoskeleton Data Disease Embryonic Development Endothelial Cells Endothelium 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 Macrophage Activation Malignant Neoplasms Mediating Mediator Methods Molecular Molecular Target Outcome Participant Pathway interactions Patients Pharmaceutical Preparations Phase Phenotype Phosphorylation 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 biomarker identification cancer cell cell motility chemoradiation cytokine effector T cell head and neck cancer patient high risk immunological status immunoregulation immunotherapy trials in vivo inhibitor intravital microscopy knock-down migration monocyte neoplastic cell novel participant enrollment pharmacologic potential biomarker pre-clinical predictive marker radiation response radiological imaging receptor recruit response response biomarker side effect therapeutic target therapy resistant trafficking transcriptome sequencing treatment response 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 对于高危头颈癌（HNSCC）患者来说，治疗耐药仍然是一个具有挑战性的问题。目前免疫检查点抑制剂的试验产生了次优的反应率，这可能是由于。 TME 因素可显着调节免疫景观的组成、表型和功能。独特的免疫抑制细胞亚型优先招募到肿瘤床可能发挥重要作用有助于促进肿瘤的生长和进展。调节免疫细胞进入、稳定性和激活状态的屏障，但其机制基础 EphB4 受体酪氨酸激酶及其配体 EFNB2 定义了新的分子，但仍知之甚少。尽管已经在早期胚胎发育中的细胞迁移和血管生成中研究了它们，关于它们在调节癌症免疫微环境中的作用，我们的初步数据还很少发表。显示 HNSCC 富含调节性 T 细胞 (Treg) 和肿瘤相关巨噬细胞 (TAM)，两者其中 EFNB2 在 RT 后在肿瘤血管系统中上调，而 EphB4 则有助于抵抗。在 Tregs 和 TAM 上表达，在所有免疫细胞中，Treg 和 TAM 对任一免疫细胞最敏感在 RT 的背景下，使用 TNYL-RAW 或基因敲低内皮 EFNB2 进行药理抑制。因此，RT 上调肿瘤血管内皮细胞上的 EFNB2，从而发挥作用优先招募表达 EphB4 的 Tregs 和 TAM 阻断 EphB4-EFNB2 信号传导。肿瘤内皮屏障会阻碍Tregs和TAMs浸润和促进癌细胞存活的能力在Aim1中，我们将分析免疫之间相互作用的机制结果。细胞 EphB4 和内皮 EFNB2 对免疫跨内皮运输、存活、极化和免疫细胞的分化以及内皮细胞对 RT 的血管正常化。使用药物抑制剂以及内皮细胞上 EFNB2 缺失或 EphB4 缺失的 GEMM 目标 2 将研究 Tregs 或 TAM 之间相互作用触发的细胞和分子机制。表达内皮 EFNB2 和 EphB4 的免疫细胞对 RT 反应的免疫细胞过程的影响将进行 STAT3、AKT 和 Erk 通路的靶向抑制。根据我们的初步数据，Aim 3 将使用来自人体临床试验的组织。在单独用药或联合用药前后使用 sEphB4-HSA（一种目前处于 I 期和 II 期试验的抑制剂）单独放化疗将有助于识别驱动抗肿瘤免疫的分子介质。这些研究还将共同阐明该疗法的分子和细胞参数。 EphB4-EFNB2 抑制剂，并将允许使用 EphB4- 识别潜在的预测标记 EFNB2 抑制剂。