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

• 批准号: 9926230
• 负责人: VICTOR H ENGELHARD
• 金额: $ 47.96万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9926230
• 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; Immunologics; 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; Prognostic Marker; Proteins; Publishing; Research Personnel; Role; Signal Transduction; Solid Neoplasm; Source; Structure; T-Lymphocyte; Technical Expertise; Technology; Testing; Therapeutic; Tissues; Treatment Efficacy; Tumor-Associated Vasculature; Tumor-infiltrating immune cells; Up-Regulation; Vaccination; Vascular Endothelial Growth Factors; Work; anergy; angiogenesis; base; bevacizumab; cell motility; cytokine; immune checkpoint blockade; immunoregulation; improved; improved outcome; in vivo imaging; knock-down; migration; novel; overexpression; pleiotropism; receptor; receptor expression; response; single cell analysis; success; tool; trafficking; tumor; tumor growth; tumor immunology; tumor microenvironment; tumor-immune system interactions

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CD 8 T细胞（TCD 8）的存在是患者生存的积极预后指标，但 TCD 8在许多肿瘤中的表达很差。虽然这可能是由于肿瘤内 在细胞增殖的情况下，也是只有非常小部分的过继转移的TCD 8或CAR-T进入细胞的情况。 肿瘤的我们已发表的和初步的数据表明，归巢受体配体（HRL）表达的肿瘤 血管系统是次优的，并且可以通过解除免疫抑制来增强TCD 8进入肿瘤。 我们的工作还提出了一个正反馈模型，其中来自新进入的肿瘤内效应物活性 需要TCD 8来维持HRL表达并维持新产生的效应物的进入。所开展工作 其他人认为促血管生成因子如VEGF可能通过多种途径限制TCD 8的浸润， 机制，包括紊乱的血管结构，干扰内皮细胞中的细胞因子信号传导 诱导HRL上调和肿瘤内免疫抑制。然而，这些不同的方面 血管生成的影响直接TCD 8效应进入肿瘤仍有待确定。也还有 对先天性免疫细胞和肿瘤内抗原在增强TCD 8进入中的作用知之甚少 效应器该多PI R 01应用程序是两名研究者之间的合作，具有互补性 专业知识恩格尔哈德实验室已经确定：基于归巢受体（HR）的TCD 8效应子亚群 表达模式;肿瘤血管系统上HRL表达的模式;以及介导HRL表达的HR/HRL对。 TCD 8效应物迁移到肿瘤中。凯利实验室一直专注于开发工具和使用工程 研究内皮在疾病中的作用的方法。利用噬菌体展示技术， hornerin是一种在肿瘤血管中过表达的新型非VEGF诱导蛋白。霍纳林击倒领先 血管正常化和增加灌注而不损失血管。霍纳林可能是一个理想的 以促进血管正常化，而不产生混杂的多效性效应 当抑制VEGF时观察到。这两位研究人员将使用这些新颖的工具和专业知识来了解 肿瘤内抗原、肿瘤血管和肿瘤细胞如何调节TCD 8直接进入肿瘤 微环境目的1将确定肿瘤内免疫调节机制对HRL的影响 肿瘤血管的表达和外源性TCD 8效应物运输。目标2将决定 促血管生成因子和肿瘤血管正常化对肿瘤血管系统HRL表达的影响， 外源性TCD 8效应物运输。目的3将确定先天性免疫细胞和肿瘤内抗原在 促进TCD 8效应物运输到肿瘤中。总的来说，这项工作将阐明限制移民的因素。 肿瘤特异性T细胞在疫苗接种或过继转移后进入肿瘤，并提出了增强 它们的渗透和随后的治疗功效。这些信息可以与活动的 疫苗接种或基于过继转移的免疫疗法，以增强其在更广泛的 癌症患者。