Investigating T Cell Egress via Lymphatic Vessels in Melanoma

研究黑色素瘤中 T 细胞通过淋巴管的排出

• 批准号: 10563146
• 负责人: Amanda W. Lund
• 金额: $ 38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563146
• 关键词: Affinity; Antibodies; Antigens; Automobile Driving; Biological; Biological Markers; Biological Models; CD8-Positive T-Lymphocytes; CTLA4 gene; CXCR4 gene; CXCR6 gene; Cell Count; Cells; Clinical; Cytotoxic T-Lymphocytes; Data; Future; G-Protein-Coupled Receptors; Heterogeneity; Homing; Immune; Immune Evasion; Immunosuppression; Immunotherapy; In Situ; Interferon Type II; Label; Leukocytes; Ligands; Lymphatic; Lymphocyte; Mediating; Metabolism; Metastatic Melanoma; Molecular; Mus; Mutation; Neoplasm Metastasis; PD-1/PD-L1; Pathway interactions; Patients; Play; Population; Pre-Clinical Model; Predisposition; Proteins; Publishing; Resistance; Resolution; Role; Route; Signal Transduction; Specificity; Stromal Cell-Derived Factor 1; T cell infiltration; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Transgenic Organisms; Tumor Antigens; Tumor Escape; Tumor Expansion; Tumor Immunity; Work; anti-tumor immune response; cancer care; candidate identification; chemokine; chemokine receptor; clinical efficacy; clinical translation; clinically actionable; cytotoxic CD8 T cells; effector T cell; exhaustion; immune checkpoint; immune checkpoint blockade; improved; in vivo; lymphatic vasculature; lymphatic vessel; melanoma; novel; novel strategies; patient stratification; prevent; recruit; residence; response; synergism; targeted agent; targeted treatment; treatment response; tumor; tumor microenvironment

Project Summary The clinical efficacy of immune checkpoint blockade (ICB) in a subset of metastatic melanoma patients has catalyzed a revolution in cancer care leading to its application to a variety of other tumor types. The discrepancy in response to ICB between, and even within, tumor types, however, indicates that additional mechanisms of suppression must be targeted to expand utility of these therapies. Recent biomarker studies, indicate that presence of cytotoxic T cells (CTLs) within tumor microenvironments enriches for patients who are likely to respond, suggesting that efforts to improve intratumoral accumulation of tumor-specific CTLs might enhance response to therapy. The current proposal will examine mechanisms regulating T cell exit from melanoma and propose inhibition of egress as a novel strategy to improve T cell retention and thus response to ICB. We will test the hypothesis that tumor-associated lymphatic vessels influence intratumoral CTL pools by directing their egress. Transgenic mice expressing a photoconvertible protein will be used to in situ label and in vivo track tumor resident lymphocyte populations. Using this model system paired with transgenic T cells and altered antigen ligands, we will determine the role antigen encounter plays in determining which cells egress from melanoma microenvironments to delineate how T cell egress from tumors contributes to the diversity of the intratumoral T cell repertoire. Our preliminary data indicates that T cells specific for tumor antigens egress from tumors indicating that inhibition of tumor exit, to retain these T cells, might improve response to immunotherapy. To test this, we will determine the functional significance of candidate chemokine receptors, CXCR4 and CXCR6, which we predict regulate T cell egress and retention respectively. We will determine the therapeutic synergy of combining agents targeting these pathways with immune checkpoint blockade. Finally, we have shown that disrupting lymphatic vessel crosstalk with CTLs, mediated by IFNγ, improves tumor control. We will explore the role of IFNγ-mediated bidirectional crosstalk in regulating T cell egress through lymphatic vessels and thus propose T cell egress as a mechanism of immune resolution coopted by tumor microenvironments to mediate immune evasion. Taken all together, we propose that CTLs integrate multiple signals in melanoma microenvironments that tune their accumulation and function in concert with the lymphatic vasculature. We predict that inhibition of CTL egress represents a tractable clinical strategy that can synergize with therapies targeting additional immunosuppressive mechanisms (e.g. metabolism and exhaustion), and mechanistic studies described herein will provide the rationale for future clinical translation.

项目概要 免疫检查点阻断（ICB）对转移性黑色素瘤患者亚群的临床疗效 催化了癌症治疗的革命，导致其应用于多种其他肿瘤类型。 然而，肿瘤类型之间甚至内部对 ICB 的反应存在差异，这表明额外的 必须针对抑制机制来扩大这些疗法的效用， 表明肿瘤微环境中细胞毒性 T 细胞 (CTL) 的存在丰富了患有以下疾病的患者： 可能会产生反应，这表明改善肿瘤特异性 CTL 的瘤内积累的努力可能会 增强对治疗的反应。目前的提案将研究调节 T 细胞退出的机制。 黑色素瘤并提出抑制出口作为改善 T 细胞保留和反应的新策略 我们将检验肿瘤相关淋巴管影响肿瘤内 CTL 库的假设。 通过引导它们的出口，表达光转换蛋白的转基因小鼠将被用于原位标记。 并使用该模型系统与转基因 T 配对进行体内追踪肿瘤驻留淋巴细胞群。 细胞和改变的抗原配体，我们将确定抗原相遇在确定哪些细胞中所起的作用 从黑色素瘤微环境中流出，以描述 T 细胞从肿瘤中的流出如何促进 我们的初步数据表明肿瘤内 T 细胞具有特异性。 抗原从肿瘤中流出表明抑制肿瘤流出以保留这些 T 细胞可能会改善 为了测试这一点，我们将确定候选趋化因子的功能意义。 我们预测 CXCR4 和 CXCR6 受体分别调节 T 细胞的流出和保留。 确定针对这些途径的联合药物与免疫检查点的治疗协同作用 最后，我们发现干扰素γ介导的淋巴管与CTL的串扰， 我们将探讨 IFNγ 介导的双向串扰在调节 T 细胞中的作用。 通过淋巴管流出，因此提出 T 细胞流出作为免疫解决机制 综上所述，我们提出 CTL 被肿瘤微环境利用来介导免疫逃避。 在黑色素瘤微环境中整合多个信号，协调调节它们的积累和功能 我们预测抑制 CTL 排出是一种易于处理的临床策略。 可以与针对其他免疫抑制机制（例如代谢和 耗尽），本文描述的机制研究将为未来的临床转化提供理论依据。

项目成果

Standing Watch: Immune Activation and Failure in Melanoma Sentinel Lymph Nodes.

• DOI: 10.1158/1078-0432.ccr-22-0214
• 发表时间: 2022-05-13
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research

Be Easy and Chill: Melanoma Cells Tell Lymph Node Fibroblasts to Relax.

放松心情：黑色素瘤细胞告诉淋巴结成纤维细胞放松。

• DOI: 10.1158/0008-5472.can-22-0940
• 发表时间: 2022
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: Lund,AmandaW

Lymph node metastasis fuels systemic disease.

淋巴结转移会加剧全身性疾病。

• DOI: 10.1016/j.trecan.2022.06.003
• 发表时间: 2022
• 期刊: Trends in cancer
• 影响因子: 18.4
• 作者: Ventre,KatherineS;Karakousi,Triantafyllia;Lund,AmandaW
• 通讯作者: Lund,AmandaW

Lymph node metastasis: An immunological burden.

• DOI: 10.1084/jem.20230904
• 发表时间: 2023-09-04
• 期刊: The Journal of experimental medicine

Lymph: (Fe)rrying Melanoma to Safety.

淋巴：将黑色素瘤转移到安全的地方。

• DOI: 10.1016/j.ccell.2020.08.011
• 发表时间: 2020
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Lund,AmandaW;Soengas,MariaS
• 通讯作者: Soengas,MariaS