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.

项目摘要 在转移性黑色素瘤患者子集中免疫切除障碍物（ICB）的临床效率具有 催化了癌症护理的革命，导致其应用于其他各种肿瘤类型。这 然而 必须针对抑制机制来扩大这些疗法的效用。最近的生物标志物研究， 表明肿瘤微环境中的细胞毒性T细胞（CTL）的存在丰富 可能做出反应，表明改善肿瘤特异性CTL的肿瘤内积累的努力可能 增强对治疗的反应。当前的建议将检查调节T细胞退出的机制 黑色素瘤和提议抑制出口作为改善T细胞保留率的新策略，从而反应 到ICB。我们将检验以下假设：肿瘤相关淋巴视频会影响肿瘤内CTL池 通过指导他们的出口。表达光关注蛋白的转基因小鼠将用于原位标签 和体内肿瘤居民淋巴细胞种群。使用此模型系统与转基因T配对 细胞和改变的抗原配体，我们将确定抗原遇到在确定哪些细胞中的作用 来自黑色素瘤微环境的出口到描述肿瘤中T细胞出口的贡献 肿瘤内T细胞库的多样性。我们的初步数据表明T细胞针对肿瘤 从肿瘤中出口抗原，表明抑制肿瘤出口以保留这些T细胞，可能会改善 对免疫疗法的反应。为了测试这一点，我们将确定候选趋化因子的功能意义 我们预测受体CXCR4和CXCR6分别调节T细胞出口和保留率。我们将 确定将这些途径靶向这些途径与免疫检查点的剂的治疗协同作用 glocade。最后，我们已经表明，与IFNγ介导的CTL串扰淋巴管串扰， 改善肿瘤控制。我们将探讨IFNγ介导的双向串扰在调节T细胞中的作用 通过淋巴管出口，因此提出了T细胞出口作为免疫分辨率的机制 由肿瘤微环境配合以介导免疫进化。全部完成，我们建议CTL 在黑色素瘤微环境中集成了多个信号，以调整其共同的积累和功能 与淋巴脉管系统。我们预测，CTL出口的抑制代表了一种可拖延的临床策略 这可以与针对其他免疫抑制机制的疗法协同作用（例如，代谢和 精疲力尽），本文所述的机械研究将为将来的临床翻译提供理由。

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