Lymph node-like vasculature and naive T cell infiltration into tumors

淋巴结样脉管系统和幼稚 T 细胞浸润肿瘤

• 批准号: 8813956
• 负责人: VICTOR H ENGELHARD
• 金额: $ 20.62万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8813956
• 关键词: Address; Blood; Blood Vessels; Breast Cancer Patient; CCL19 gene; CCL21 gene; CD8B1 gene; Cancer Control; Cancer Patient; Cells; Data; Development; Disease; Effectiveness; Endothelial Cells; Enzymes; Future; Generations; Glycoproteins; Goals; Health; High Endothelial Venule; Homing; Human; Immune; Immunosuppression; Immunotherapy; In Situ; Infiltration; Inflammatory; Integrins; Interferon Type II; Investigation; L-Selectin; Ligands; Lymphoid; Lymphoid Tissue; Malignant Neoplasms; Mediating; Mus; Natural Killer Cells; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Organ; Patients; Peripheral; Prognostic Marker; Receptor Signaling; Regulation; Reporting; Role; Scaffolding Protein; Selectins; Signal Transduction; Solid Neoplasm; Source; Structure; T-Cell Activation; T-Lymphocyte; Tissues; Tumor Immunity; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-Beta; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Tumor-Infiltrating Lymphocytes; Vaccination; Work; base; blood vessel development; carbohydrate structure; chemokine; chemokine receptor; insight; lymph nodes; malignant breast neoplasm; novel; receptor; receptor binding; research study; subcutaneous; tumor

DESCRIPTION (provided by applicant): Limited representation of intratumoral immune cells is a major barrier to tumor control distinct from the barrier of immunosuppression. Understanding and overcoming this limitation will enable us to extend the effectiveness of many immunotherapies to a broader cross-section of cancer patients. It has been assumed that all tumor- infiltrating lymphocytes are effectors that differentiate in tumor-draining lymph nodes (LN) and subsequently enter the tumor. However, we showed that naive CD8 T cells (TCD8) enter tumors directly, where they differentiate into functional effectors. Naive TCD8 infiltration depends on L-selectin and CCR7, and on the development of tumor blood vessels that express peripheral node addressing (PNAd) and the chemokine CCL21 and resemble LN high endothelial venules. We have also identified organized tertiary lymphoid tissue (TLO) in juxtaposition to this LN-like vasculature. PNAd+ LN-like vasculature has been reported in human solid tumors in association with TLO-like tissue, and correlated with longer metastasis-free, disease-free, and overall survival in breast cancer patients. These data suggest that induction of LN-like vasculature could bolster anti- tumor immunity by enhancing the infiltration and in situ activation of naive TCD8. Induction of high endothelial venules in LN is controlled by lymphotoxin-ß receptor signaling. However, we found that CCL21 expression depends on IFNγ secreted by TCD8 effectors, while PNAd expression is controlled by lymphotoxin-α3. This suggests that early infiltration of effectors induces LN-like vasculature, which in turn supports a self-sustaining recruitment of naïve T cells that differentiate within the tumor. The aims of this application are: (1) to determine how TNF receptor ligands regulate the expression of PNAd on tumor vasculature. We will evaluate which scaffolding proteins and enzymes are responsible for tumor associated PNAd. We will also determine if TNFα and lymphotoxin-α3 act redundantly to induce PNAd expression in subcutaneous tumors, since both are ligands for TNF receptors 1 and 2; (2) to determine how the expression of CCL21 in tumors is regulated. We will determine how IFNγ controls the expression of CCL21 by gp38+CD31neg cell and endothelial cells in IP tumors. We will also identify mechanisms controlling CCL21 expression in SC tumors; (3) to evaluate the organization and function of TLO-like structures that form in association with LN-like vasculature in tumors. We will evaluate the role of gp38+CD31neg cells as organizers of TLO in tumors, and the factors that influence their activity. We will also determine whether these TLO serve as a locus for positive or negative regulation of anti- tumor immunity. As an R21 application, our purpose is to conduct experiments that will distinguish among different novel mechanisms that control expression of these molecules, enabling development of a future R01 application to investigate means to manipulate them to enhance anti-tumor immunity and cancer control.

描述（由申请方提供）：肿瘤内免疫细胞的有限表达是肿瘤控制的主要障碍，与免疫抑制障碍不同。了解并克服这一限制将使我们能够将许多免疫疗法的有效性扩展到更广泛的癌症患者。已经假设所有的肿瘤浸润淋巴细胞都是在肿瘤引流淋巴结（LN）中分化的效应子。 然后进入肿瘤然而，我们发现初始CD 8 T细胞（TCD 8）直接进入肿瘤，在那里它们分化成功能性效应子。初始TCD 8浸润依赖于L-选择素和CCR 7，以及表达外周淋巴结寻址（PNAd）和趋化因子CCL 21并类似于LN高内皮微静脉的肿瘤血管的发展。我们还发现了与LN样血管并列的有组织的三级淋巴组织（TLO）。已在人实体瘤中报道了PNAd+ LN样脉管系统与TLO样组织相关，并且与乳腺癌患者中较长的无转移、无疾病和总生存期相关。这些数据表明，LN样脉管系统的诱导可以通过增强初始T ⑶ 8的浸润和原位活化来增强抗肿瘤免疫。LN中高内皮微静脉的诱导是由光敏素-β受体信号控制的。然而，我们发现CCL 21的表达依赖于TCD 8效应子分泌的IFNγ，而PNAd的表达受α3光毒素控制。这表明效应子的早期浸润诱导LN样血管，这反过来又支持在肿瘤内分化的幼稚T细胞的自我维持募集。本研究的目的是：（1）探讨肿瘤坏死因子受体配体对肿瘤血管PNAd表达的调节作用。我们将评估哪些支架蛋白和酶负责肿瘤相关PNAd。我们还将确定TNFα和光敏素-α3是否在皮下肿瘤中冗余地诱导PNAd表达，因为两者都是TNF受体1和2的配体;（2）确定肿瘤中CCL 21的表达是如何调节的。我们将确定IFNγ如何控制IP肿瘤中gp 38 + CD 31 neg细胞和内皮细胞表达CCL 21。我们还将确定控制SC肿瘤中CCL 21表达的机制;（3）评估与肿瘤中LN样血管系统相关的TL 0样结构的组织和功能。我们将评估gp 38 + CD 31 neg细胞在肿瘤中作为TLO组织者的作用，以及影响其活性的因素。我们还将确定这些TLO是否作为抗肿瘤免疫的正向或负向调节位点。作为R21应用，我们的目的是进行实验，区分控制这些分子表达的不同新机制，从而能够开发未来的R 01应用，以研究操纵它们以增强抗肿瘤免疫和癌症控制的方法。