Role of intratumoral high endothelial venules in tumor immunity

瘤内高内皮微静脉在肿瘤免疫中的作用

• 批准号: 10590624
• 负责人: Masanobu Komatsu
• 金额: $ 36.71万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10590624
• 关键词: Adoptive Transfer; Affect; Antigens; Area; B-Lymphocytes; Blood Circulation; Blood Vessels; Breast Adenocarcinoma; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Patient; Cell Density; Cells; Circulation; Clinical; Clinical Research; Dendritic Cells; Development; Drug Delivery Systems; Endothelial Cells; Environment; Enzyme-Linked Immunosorbent Assay; Exclusion; Exhibits; Favorable Clinical Outcome; Genetic Models; High Endothelial Venule; Human; Immune; Immune checkpoint inhibitor; Immune mediated destruction; Immunofluorescence Immunologic; Immunotherapy; Infiltration; Invaded; Laboratories; Link; Lymphocyte; Lymphocytic Infiltrate; Malignant Neoplasms; Mammary Neoplasms; Molecular; Monomeric GTP-Binding Proteins; Mus; Natural regeneration; Nature; Neoplasms in Vascular Tissue; Outcome Study; PD-1/PD-L1; Paper; Patients; Population; Process; Prognosis; Publishing; RAS genes; Reporting; Role; Shapes; Specimen; Structure; T-Lymphocyte; Therapeutic Effect; Tumor Antigens; Tumor Immunity; Tumor Suppression; Vascular Endothelial Cell; anti-PD1 therapy; attenuation; cancer immunotherapy; cancer infiltrating T cells; cancer survival; cancer therapy; cancer type; cell type; checkpoint inhibition; checkpoint therapy; chemotherapy; cytokine; density; effector T cell; gain of function; immunogenic; improved; loss of function; lymph nodes; malignant breast neoplasm; melanoma; novel; patient response; patient subsets; programs; recruit; response; success; tertiary lymphoid organ; transcriptome sequencing; treatment strategy; tumor; tumor microenvironment; venule

Project Summary Immune checkpoint inhibition emerged as promising cancer treatment strategies. However, only a subset of patients respond to these therapies at present. Significant clinical evidence indicates that abundant tumor infiltration of effector T cells and B cells is a prerequisite for the success of the immune checkpoint inhibition therapies. However, these lymphocytes are largely excluded from many patients' tumors, which makes the tumor unresponsive to the immunotherapies. High endothelial venules (HEV) are specialized venules that serve as gateways for naïve lymphocyte recruitment, and these blood vessels can develop ectopically in tumors. High HEV density in tumors correlate with favorable clinical outcomes, suggesting that the promotion of intratumoral HEV formation would offer a novel opportunity to improve immunotherapies. The small GTPase R-Ras balances angiogenic sprouting and vessel maturation, and normalizes tumor blood vessels. Several lines of evidence indicate the importance of R-Ras for the formation of intratumoral HEVs. We hypothesize that intratumoral HEVs shape the tumor immune landscape through efficient recruitment of lymphocytes, thereby creating the immunostimulatory microenvironment favorable for immune checkpoint inhibition therapies. We propose a critical role of R-Ras in this process by facilitating HEV formation in tumors. Using novel genetic models of loss- and gain-of-function of R-Ras in endothelial cells, Aim 1 will demonstrate that R-Ras facilitates the formation of HEVs within the tumor vasculature and determine how these HEVs affect the tumor infiltration of T cells, B cells, dendritic cells, and other immune cell types in immunogenic mouse mammary tumor and melanoma. The influence of intratumoral HEVs on cytokine environment will also be determined. The analyses will be conducted by immunofluorescence, ELISA, FACS, and RNAseq. Clinical cancer specimens will be examined to corroborate the findings from the mouse studies. Aim 2 will functionally characterize tumor HEVs and analyze intratumoral priming of HEV-recruited T cells to a specific antigen using adoptive transfer of naïve OT-1 T cells to OVA-expressing tumors. Aim 3 will determine how intratumoral HEVs impact the immune destruction of tumors and the responsiveness to PD-1/PD-L1 inhibition therapies. As the gateways for T cell/B cell recruitment to tumors, intratumoral HEVs are potential new targets to reprogram the tumor immune landscape and to improve patients' response to immune checkpoint inhibitors. The expected outcome of this study will provide the proof-of-concept for such ideas.

项目概要 免疫检查点抑制成为有前景的癌症治疗策略。然而，只有一个子集 目前患者对这些疗法有反应。重要的临床证据表明，丰富的肿瘤 效应T细胞和B细胞的浸润是免疫检查点抑制成功的先决条件 疗法。然而，这些淋巴细胞很大程度上被排除在许多患者的肿瘤之外，这使得肿瘤 对免疫疗法无反应。高内皮微静脉 (HEV) 是一种特殊的微静脉，充当 幼稚淋巴细胞募集的门户，这些血管可以在肿瘤中异位发育。高的 肿瘤中的 HEV 密度与良好的临床结果相关，表明促进瘤内 HEV 的形成将为改善免疫疗法提供新的机会。小 GTPase R-Ras 天平 血管生成和血管成熟，并使肿瘤血管正常化。几行证据 表明 R-Ras 对于瘤内 HEV 形成的重要性。我们假设瘤内 HEV 通过有效招募淋巴细胞来塑造肿瘤免疫景观，从而创造 有利于免疫检查点抑制疗法的免疫刺激微环境。我们提出一个关键的 R-Ras 在此过程中通过促进肿瘤中 HEV 的形成发挥作用。 使用内皮细胞中 R-Ras 功能丧失和获得的新型遗传模型，目标 1 将证明 R-Ras 促进肿瘤血管内 HEV 的形成并确定这些 HEV 如何影响 免疫原性小鼠中 T 细胞、B 细胞、树突状细胞和其他免疫细胞类型的肿瘤浸润 乳腺肿瘤和黑色素瘤。瘤内 HEV 对细胞因子环境的影响也将是 决定。分析将通过免疫荧光、ELISA、FACS 和 RNAseq 进行。临床 将检查癌症样本以证实小鼠研究的结果。目标 2 将在功能上 使用以下方法表征肿瘤 HEV 并分析 HEV 招募的 T 细胞对特定抗原的瘤内引发 将初始 OT-1 T 细胞过继转移至表达 OVA 的肿瘤。目标 3 将确定瘤内 HEV 如何 影响肿瘤的免疫破坏以及对 PD-1/PD-L1 抑制疗法的反应。 作为 T 细胞/B 细胞募集至肿瘤的门户，肿瘤内 HEV 是重新编程的潜在新靶点 肿瘤免疫景观并改善患者对免疫检查点抑制剂的反应。预期的 这项研究的结果将为这些想法提供概念验证。