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: 10444131
• 负责人: Masanobu Komatsu
• 金额: $ 37.46万
• 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/10444131
• 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; Clinical; Clinical Research; Dendritic Cells; Development; Drug Delivery Systems; Endothelial Cells; Environment; Enzyme-Linked Immunosorbent Assay; Equilibrium; Exhibits; Favorable Clinical Outcome; Genetic Models; High Endothelial Venule; Human; Immune; Immune checkpoint inhibitor; Immune mediated destruction; Immunofluorescence Immunologic; Immunotherapy; Infiltration; Laboratories; Link; Lymphocyte; 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; Tumor-infiltrating immune cells; Vascular Endothelial Cell; anti-PD1 therapy; attenuation; cancer immunotherapy; cancer survival; cancer therapy; cancer type; cell type; checkpoint inhibition; checkpoint therapy; chemotherapy; cytokine; density; effector T cell; gain of function; immunogenic; improved; lymph nodes; malignant breast neoplasm; melanoma; novel; patient response; patient subsets; 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.

项目摘要 免疫检查点抑制作用作为承诺的癌症治疗策略出现。但是，只有一个子集 患者目前对这些疗法做出反应。大量临床证据表明肿瘤丰富 效应T细胞和B细胞的渗透是免疫检查点抑制成功的先决条件 疗法。但是，这些淋巴细胞在很大程度上被排除在许多患者的肿瘤中，这使得肿瘤 对免疫疗法无反应。高内皮静脉（HEV）是专门的静脉 幼稚淋巴细胞募集的门户，这些血管可以在肿瘤中生态发展。高的 肿瘤中的HEV密度与有利的临床结果相关，表明肿瘤内促进 HEV组将提供一个新的机会来改善免疫疗法。小GTPase R-RAS平衡 血管生成发芽和血管成熟，并使肿瘤血管归一化。几条证据 指标R-RAS对形成肿瘤内HEV的重要性。我们假设肿瘤内HEV 通过有效募集淋巴细胞来塑造肿瘤免疫景观，从而创建 免疫刺激性微环境有利于免疫抑制作用疗法。我们提出了一个批判 R-RAS在此过程中的作用通过支持肿瘤中的HEV形成。 使用内皮细胞中R-RAS损失和功能获得的新型遗传模型，AIM 1将证明 R-RAS促进了肿瘤脉管系统中HEV的形成，并确定这些HEV如何影响 免疫小鼠中T细胞，B细胞，树突状细胞和其他免疫球类型的肿瘤浸润 乳腺肿瘤和黑色素瘤。肿瘤内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 将检查癌症标本以证实小鼠研究的发现。 AIM 2将在功能上 表征肿瘤HEV并分析使用HEV合并的T细胞的肿瘤内启动到特定的抗原使用 将OT-1 T细胞转移到表达OVA的肿瘤上。 AIM 3将决定肿瘤内HEV 影响肿瘤的免疫学和对PD-1/PD-L1抑制疗法的反应性。 作为T细胞/B细胞募集到肿瘤的门户，肿瘤内HEV是重新编程的潜在新目标 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 这项研究的结果将为此类想法提供概念验证。