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: 10801106
• 负责人: Jose R Conejo-Garcia
• 金额: $ 38.49万
• 依托单位: DUKE UNIVERSITY
• 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 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10801106
• 关键词: cell; dependent; anti; tumor; immunity

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 在肿瘤床内，T 细胞和 B 细胞经常相互作用形成高度组织化的结构，类似于 淋巴结，称为三级淋巴结构 (TLS)，与更好的 许多肿瘤的结果。 TFH 细胞对于生发中心的形成至关重要 体液反应，我们的新数据表明 TFH 细胞成为体液反应的主要生产者 接种疫苗后的 CXCL13 和 TNFS14/LIGHT。 TLS 的组装和维护应该 因此取决于 TFH 反应。我们的新数据表明，富含特殊 AT T 细胞中序列结合蛋白 1 (Satb1) 的特异性消除可导致 TFH 增强 分化和增强的 Ag 特异性体液反应，这与 同时进行 ICOS 和 PD-1 去抑制。因此，我们的中心假设是 LIGHT+CXCL13+ TFH 细胞的形成以及随后 TLS 在癌症中的协调是 CD4 T 细胞中的 Satb1 沉默通过去抑制 TFH 细胞中的 ICOS 和 通过 PD-1 抑制 Foxp3+PD-1highCXCR5+ T 滤泡调节 (TFR) 细胞形成 上调。因此，TGF-β 反而增强了 TFH 细胞的生成，并且促进了 TFH 细胞的生成。 通过 Satb1 抑制形成 TLS。 在目标 1 中，我们将定义 TFH 期间 SATB1 依赖性 ICOS 表达的作用 差异化。通过 ChIP-PCR 和 Satb1-competent 与 Satb1-competent 的功能分析 体内缺乏T细胞，我们将证实一种新的表观遗传机制，其中主 基因组组织者 Satb1 控制 ICOS 表达，导致 TFH 分化增强 Satb1 的缺失。 在目标 2 中，我们将确定 SATB1 在 TGF-β 驱动、Treg 依赖性 TFH 中的作用 差异化。在这里，我们将结合遗传操作和现有的转基因模型 确定 TGF-β 驱动 TFH 分化的机制在多大程度上是 Satb1- 和 PD-1- 依赖性，以需要减少 TFR 形成的方式。 在目标 3 中，我们将概括导致形成和保护活性的机制 TLS 在卵巢癌体内的作用。通过利用独特的转基因模型，我们的卵巢癌- 特定的 CAR T 细胞和来自新鲜分离卵巢的可行单细胞悬浮液 对于癌症，我们将定义一个新的 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 SATB1 控制的肿瘤床中 TFH 细胞的生成依赖于 TGF-β 方式。在体内重述这些机制将为更有效的研究铺平道路 免疫疗法旨在通过以下方式促进体液和 T 细胞的联合反应： 在不可切除/转移性肿瘤中协调 TLS，并可能导致识别 肿瘤床自发产生具有抗肿瘤活性的抗体。