Manipulating microenvironment and vasculature to enhance T cell infiltration into tumors

操纵微环境和脉管系统以增强 T 细胞浸润肿瘤

基本信息

批准号：
10625302
负责人：
VICTOR H ENGELHARD
金额：
$ 50.72万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10625302
关键词：
Adoptive Cell Transfers Adoptive Transfer Anatomy Angiogenesis Inhibition Angiogenic Factor Angiogenic Proteins Attenuated Biology Blood Circulation Blood Vessels CD8-Positive T-Lymphocytes Cancer Patient Cell physiology Cells Cellular Immunology Clinical Collaborations Color Cytokine Signaling Data Disease Dose Down-Regulation Effectiveness Endothelial Cells Endothelium Engineering Feedback Flow Cytometry Generations Hemorrhage Homing Hypoxia Imaging Techniques Immune Immunity Immunosuppression Immunotherapy Infiltration Inflammatory Knowledge Ligands Liquid substance Mediating Modeling Molecular Neoplasms in Vascular Tissue Outcome Patients Pattern Perfusion Peripheral Phage Display Physiological Play Population Process Proliferating Proteins Publishing Research Personnel Role Signal Transduction Solid Neoplasm Source Starvation Structure T cell infiltration T-Lymphocyte Technical Expertise Technology Testing Therapeutic Tissues Treatment Efficacy Tumor-Associated Vasculature Tumor-infiltrating immune cells Up-Regulation Vaccination Vascular Endothelial Growth Factors Vegf inhibition Work anergy angiogenesis bevacizumab cell motility chimeric antigen receptor T cells cytokine immune cell infiltrate immune checkpoint blockade immunoregulation improved improved outcome in vivo imaging knock-down migration novel overexpression pleiotropism prognostic indicator receptor receptor expression response single cell analysis success tool trafficking tumor tumor growth tumor immunology tumor microenvironment tumor-immune system interactions

项目摘要

The presence of CD8 T cells (TCD8) in tumors is a positive prognostic indicator of patient survival, but representation of TCD8 in many tumors is poor. While this could be a consequence of poor intratumoral proliferation, it is also the case that only a very small fraction of adoptively transferred TCD8 or CAR-T enter tumors. Our published and preliminary data indicates that homing receptor ligand (HRL) expression on tumor vasculature is suboptimal and that entry of TCD8 into tumors can be enhanced by relief of immunosuppression. Our work also suggests a positive feedback model in which intratumoral effector activity from newly entering TCD8 is needed to maintain HRL expression and sustain entry of newly arising effectors. Work conducted by others has suggested that pro-angiogenic factors such as VEGF may limit TCD8 infiltration by multiple mechanisms, including disorganized vascular structure, interference with cytokine signaling in endothelial cells to induce HRL upregulation, and suppression of intratumoral immunity. However, how these different aspects of angiogenesis influence direct TCD8 effector entry into tumors remains to be determined. There is also still little understanding of the roles that innate immune cells and intratumoral Ag play in augmenting entry of TCD8 effectors. This multi-PI R01 application is a collaboration between two investigators with complementary expertise. The Engelhard lab has identified: subpopulations of TCD8 effectors based on homing receptor (HR) expression pattern; the patterns of HRL expression on tumor vasculature; and the HR/HRL pairs that mediate TCD8 effector migration into tumors. The Kelly lab has focused on developing tools and using engineering approaches to study the role of the endothelium in disease. Using phage display technology, they identified hornerin, a novel non-VEGF induced protein overexpressed on tumor vasculature. Hornerin knockdown leads to vessel normalization and increased perfusion without loss of blood vessels. Hornerin may be an ideal molecule to attenuate in order to promote vessel normalization without the confounding pleiotropic effects observed when inhibiting VEGF. These two investigators will use these novel tools and expertise to understand how the direct entry of TCD8 into tumors is regulated by intratumoral Ag, tumor vasculature, and tumor microenvironment. Aim 1 will determine the impact of intratumoral immunoregulatory mechanisms on HRL expression on tumor vasculature and on exogenous TCD8 effector trafficking. Aim 2 will determine the impact of pro-angiogenic factors and tumor vessel normalization on HRL expression on tumor vasculature and on exogenous TCD8 effector trafficking. Aim 3 will determine the role of innate immune cells and intratumoral Ag in promoting TCD8 effector trafficking into tumors. Overall, this work will illuminate factors that limit the migration of tumor-specific T cells into tumors after vaccination or adoptive transfer, and suggest approaches to enhance their infiltration and subsequent therapeutic efficacy. This information may be used in conjunction with active vaccination or adoptive transfer-based immunotherapies to enhance their efficacy in a broader spectrum of cancer patients.

肿瘤中CD8 T细胞（TCD8）的存在是患者存活的积极预后指标，但在许多肿瘤中TCD8的表示。虽然这可能是肿瘤内差的结果扩散，也只有很小的一小部分转移的TCD8或CAR-T进入肿瘤。我们发表的和初步的数据表明，肿瘤上的归巢受体配体（HRL）表达脉管系统是次优的，可以通过缓解免疫抑制来增强TCD8进入肿瘤。我们的工作还提出了一个积极的反馈模型，其中新进入的肿瘤内效应子活动需要TCD8来维持HRL表达并维持新出现的效应子的进入。进行的工作其他人提出，诸如VEGF之类的促血管生成因素可能会限制多个TCD8的渗透机制，包括混乱的血管结构，干扰内皮细胞中细胞因子信号的干扰诱导HRL上调和抑制肿瘤内免疫。但是，这些不同的方面如何血管生成影响直接TCD8效应子进入肿瘤仍有待确定。还有对先天免疫细胞和肿瘤内AG在增强TCD8进入中发挥的作用很少了解效应子。该多PI R01应用程序是两个与互补的调查员之间的合作专业知识。恩格哈德实验室已经确定：基于归巢受体（HR）的TCD8效应子的亚群表达模式； HRL表达在肿瘤脉管系统上的模式；和介导的HR/HRL对 TCD8效应子迁移到肿瘤中。凯利实验室（Kelly Lab）专注于开发工具并使用工程研究内皮在疾病中的作用的方法。他们使用噬菌体显示技术确定 Hornerin是一种新型的非VEGF诱导蛋白，对肿瘤脉管系统过表达。霍纳林敲门领先使血管归一化和灌注增加而不会流失。霍纳林可能是理想的分子减弱以促进血管归一化而不混杂的多效效应抑制VEGF时观察到。这两个调查人员将使用这些新颖的工具和专业知识来了解 TCD8如何通过肿瘤内AG，肿瘤脉管系统和肿瘤的直接进入肿瘤的直接进入微环境。 AIM 1将确定肿瘤内免疫调节机制对HRL的影响肿瘤脉管系统和外源TCD8效应子运输的表达。 AIM 2将决定在肿瘤脉管系统上的HRL表达和肿瘤血管归一化和肿瘤血管归一化外源TCD8效应子运输。 AIM 3将确定先天免疫细胞和肿瘤内AG在促进TCD8效应子运输到肿瘤中。总体而言，这项工作将阐明限制迁移的因素疫苗接种或收养后，肿瘤特异性的T细胞进入肿瘤，并提出增强的方法他们的浸润和随后的治疗功效。此信息可以与Active一起使用疫苗接种或基于收养的免疫疗法，以增强其疗效癌症患者。