B cell-dependent anti-tumor immunity in ovarian cancer

卵巢癌中 B 细胞依赖性抗肿瘤免疫

• 批准号: 10231230
• 负责人: Jose R Conejo-Garcia
• 金额: $ 78.16万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10231230
• 关键词: AT Rich Sequence; Ablation; Antibodies; Antibody Formation; Antigen-Antibody Complex; Automobile Driving; B-Lymphocytes; Beds; Binding Proteins; CD19 gene; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CXCL13 gene; Cancer Intervention; Cancer Patient; Cell Differentiation process; Cells; Complex; Data; Data Set; Dendritic Cells; Disease; Epigenetic Process; FOXP3 gene; Follicular Dendritic Cells; Generations; Genetic Transcription; Genomics; Goals; High Endothelial Venule; Human; Immune; Immunoglobulin Class Switching; Immunoglobulin G; Immunotherapy; Intervention; Lead; MS4A1 gene; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mediating; Mus; Neoplasm Metastasis; NuRD complex; Outcome; Ovarian Carcinoma; PTPRC gene; Population; Production; Prognosis; Regulatory T-Lymphocyte; Repression; Role; Sampling; Signal Transduction; Structure; Structure of germinal center of lymph node; Suspensions; T cell response; T memory cell; T-Lymphocyte; The Cancer Genome Atlas; Transforming Growth Factor alpha; Transforming Growth Factor beta; Transgenic Model; Tumor Immunity; Up-Regulation; Vaccinated; Vaccination; Work; adaptive immune response; base; chimeric antigen receptor T cells; cytokine; genome-wide; immunogenic; in vivo; lymph nodes; lymphoid structures; novel; novel therapeutics; overexpression; personalized medicine; programmed cell death protein 1; programs; promoter; recruit; response; tertiary lymphoid organ; tool; tumor; tumor immunology

ABSTRACT Within tumor beds, T and B cells often interact to form highly organized structures similar to lymph nodes, termed tertiary lymphoid structures (TLS), which are associated with better outcomes in many tumors. TFH cells are crucial for the formation of germinal centers and humoral responses, and our new data show that TFH cells become the main producers of CXCL13 and TNFS14/LIGHT upon vaccination. The assembly and maintenance of TLS should be therefore dependent on TFH responses. Our new data demonstrate that Special AT-rich sequence-binding protein-1 (Satb1) ablation specifically in T cells leads to enhanced TFH differentiation and augmented Ag-specific humoral responses, which is associated with concurrent ICOS and PD-1 de-repression. Accordingly, our central hypothesis is that LIGHT+CXCL13+ TFH cell formation and, subsequently, the orchestration of TLS in cancer, is governed by Satb1 silencing in CD4 T cells by both de-repressing ICOS in TFH cells and suppressing Foxp3+PD-1highCXCR5+ T follicular regulatory (TFR) cell formation through PD-1 up-regulation. Therefore, TGF-β paradoxically enhances the generation of TFH cells and the formation of TLS through Satb1 repression. In Aim 1, we will define the role of SATB1-dependent ICOS expression during TFH differentiation. Through ChIP-PCR and functional analysis of Satb1-competent vs. Satb1- deficient T cells in vivo, we will substantiate a novel epigenetic mechanism whereby the master genomic organizer Satb1 governs ICOS expression, leading to enhanced TFH differentiation in the absence of Satb1. In Aim 2, we will determine the role of SATB1 in TGF-β-driven, Treg-dependent TFH differentiation. Here, we will combine geentic manipulation and existing transgenic models to establish to what extent the mechanism of TGF-β-driven TFH differentiation is Satb1- and PD-1- dependent, in a manner that requires decreased TFR formation. In Aim 3, we will recapitulate the mechanisms leading to the formation and protective activity of TLS in vivo in ovarian cancer. By leveraging unique transgenic models, our ovarian cancer- specific CAR T cells and our viable single-cell suspensions from freshly dissociated ovarian carcinomas, we will define a novel TGF-β → Satb1 silencing → TFH cell formation axis driving relevant anti-tumor humoral responses. Our work will exert a profound effect in the field by elucidating how epigenetic programs controlled by SATB1 govern the generation of TFH cells at tumor beds in a TGF-β-dependent manner. Recapitulating these mechanisms in vivo will pave the way for more effective immunotherapies aimed to promote combined humoral and T cell responses through the orchestration of TLS in irresectable/metastatic tumors, and could lead to the identification of antibodies with anti-tumor activity spontaneously produced at tumor beds.

抽象的 在肿瘤床中，T和B细胞经常相互作用以形成高度有组织的结构 淋巴结，称为三级淋巴结构（TLS），与更好的相关 许多肿瘤的结果。 TFH细胞对于形成生发中心和 体液反应，我们的新数据表明，TFH细胞成为主要生产者 CXCL13和TNFS14/疫苗接种后轻。 TLS的组装和维护应 因此，取决于TFH响应。我们的新数据表明了特殊的富裕 序列结合蛋白-1（SATB1）在T细胞中的消融，导致TFH增强 分化和增强AG特异性的体液反应，这与 并发ICO和PD-1去抑制。据此，我们的中心假设是 Light+ CXCL13+ TFH细胞形成，随后，TLS在癌症中的编排是 通过在CD4 T细胞中沉默的SATB1沉默来控制TFH细胞中的ICO和 通过PD-1抑制FOXP3+ PD-1HIGHCXCR5+ T卵泡调节（TFR）细胞形成 上调。因此，TGF-β矛盾地增强了TFH细胞的产生和 通过SATB1表达形成TLS。 在AIM 1中，我们将在TFH期间定义依赖SATB1的ICOS表达的作用 分化。通过CHIP-PCR和SATB1能力与SATB1-的功能分析 在体内缺乏T细胞，我们将证实一种新型的表观遗传机制 基因组组织者SATB1控制ICOS表达，从而增强了TFH的分化 缺乏SATB1。 在AIM 2中，我们将确定SATB1在TGF-β驱动的Treg依赖性TFH中的作用 分化。在这里，我们将结合Géntic操纵和现有的转基因模型 确定TGF-β驱动的TFH分化的机制在多大程度上是SATB1-和PD-1-- 取决于需要删除的TFR形成的方式。 在AIM 3中，我们将概括导致形成和保护活动的机制 卵巢癌的TLS体内。通过利用独特的转基因模型，我们的卵巢癌 - 特定的汽车T细胞和我们来自新鲜分离的卵巢的可行的单细胞悬浮液 癌，我们将定义一个新型的TGF-β→SATB1沉默→TFH细胞形成轴驱动 相关的抗肿瘤体液反应。 我们的工作将通过阐明表观遗传程序如何在该领域产生深远的影响 由SATB1控制，控制TGF-β依赖性肿瘤床上TFH细胞的产生 方式。在体内概括这些机制将为更有效的道路铺平道路 免疫疗法旨在通过促进综合体液和T细胞反应 TLS在不可切除/转移性肿瘤中的编排，并可能导致鉴定 具有抗肿瘤活性的抗体在肿瘤床上赞助。