Hijacking the Blimp1-Neuritin Axis to Promote Cancer by Follicular Regulatory T-cells

劫持 Blimp1-Neuritin 轴通过滤泡调节 T 细胞促进癌症

基本信息

批准号：
10629053
负责人：
Jianmei Wu Leavenworth
金额：
$ 20.83万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629053
关键词：
Adopted Adoptive Transfer Area Autonomic Dysfunction Autonomic nervous system Biological Assay Cancer Patient Cells FOXP3 gene Fostering Frequencies Goals Hormones Human Immune Immune Evasion Immune system Immunofluorescence Immunologic Immunotherapeutic agent In Vitro Infiltration Investigation Location Malignant - descriptor Malignant Neoplasms Modeling Mus Nature Neoplasm Metastasis Nerve Nerve Fibers PRDM1 gene Peripheral Peripheral Nerves Psychological Stress Regulation Regulatory T-Lymphocyte Reporting Research Risk Role Stains Testing Tissues Tumor Immunity Tumor Promotion Tumor-Infiltrating Lymphocytes Tumor-associated macrophages anticancer research axonal sprouting genetic signature in vivo innovation insight nerve supply neurofilament neuroregulation neurotrophic factor patient prognosis reconstitution response retroviral-mediated therapy resistant transcription factor tumor tumor growth tumor microenvironment tumor progression tumor-immune system interactions tumorigenesis

项目摘要

Project Summary Recent studies have highlighted the vital role of nerves infiltrating the tumor microenvironment (TME) in tumorigenesis and caner progression. The current research in this field is largely focused on the impact of dysfunctions of autonomic nervous system or psychological stress-induced hormone network on the malignant progression of cancer. The potential regulation of peripheral nerve system by immune cells in the TME, which subsequently influences tumorigenesis, has not been extensively studied. The overall goal of this proposal is to define how a specific Treg subset, called follicular regulatory T (TFR) cells, modulates the TME to promote cancer by producing and utilizing a neurotrophic factor, which is an unexplored area in the field of cancer research. We have recently reported the pro-tumoral activity of TFR cells, which depends on the expression of the transcription factor Blimp1 (encoded by Prdm1). Further analysis revealed that higher tumoral TFR signatures along with PRDM1 expression indicated increased malignancy and risk of metastasis in many cancers. Moreover, intratumoral TFR cells compared to conventional Treg cells and their peripheral counterparts expressed higher levels of neuritin (encoded by Nrn1), a neurotrophic factor implicated in tumorigenesis, while its mechanistic action remains largely unclear. Notably, TFR signature and PRDM1 positively correlated with NRN1 expression in cancer patients. Intratumoral TFR cells in mice with disrupted TFR suppression due to Foxp3-specific deletion of Blimp1 had substantially reduced expression of neuritin. Most importantly, tumors from these mice and mice lacking TFR cells had markedly reduced neurofilament accumulation compared to wild-type tumors, and intratumoral TFR cells were enriched with gene signatures implicated in axonogenesis. We propose to define the mechanisms by which TFR cells exploit the Blimp1-neuritin axis to regulate the TME and tumor progression, and to define the capacity of TFR-derived neuritin in promoting axonogenesis in the tumor. Findings obtained here will revolutionize our understanding of the tumor innervation and immunosuppressive TME, aiding in developing new immunotherapeutic approaches to treat cancer.

项目概要最近的研究强调了神经浸润肿瘤微环境（TME）在肿瘤发生和癌症进展。目前该领域的研究主要集中在自主神经系统或心理应激诱发的激素网络功能障碍对恶性疾病的影响癌症的进展。 TME 中免疫细胞对周围神经系统的潜在调节，随后影响肿瘤发生，尚未得到广泛研究。该提案的总体目标是定义特定的 Treg 子集（称为滤泡调节 T (TFR) 细胞）如何调节 TME 促进癌症通过产生和利用神经营养因子，这是癌症研究领域中尚未探索的领域。我们最近报道了 TFR 细胞的促肿瘤活性，这取决于转录的表达因子 Blimp1（由 Prdm1 编码）。进一步分析表明，较高的肿瘤 TFR 特征以及 PRDM1 表达表明许多癌症的恶性程度和转移风险增加。而且，与传统 Treg 细胞及其外周细胞相比，瘤内 TFR 细胞表达更高神经突蛋白（由 Nrn1 编码）的水平，这是一种与肿瘤发生有关的神经营养因子，而其机制行动在很大程度上仍不清楚。值得注意的是，TFR 特征和 PRDM1 与 NRN1 表达呈正相关在癌症患者中。由于 Foxp3 特异性缺失，TFR 抑制受到破坏的小鼠肿瘤内 TFR 细胞 Blimp1 的表达显着降低了神经突蛋白的表达。最重要的是，来自这些小鼠和小鼠的肿瘤与野生型肿瘤相比，缺乏 TFR 细胞的神经丝积累显着减少，并且瘤内 TFR 细胞富含与轴突发生有关的基因特征。我们建议定义 TFR 细胞利用 Blimp1-neuritin 轴调节 TME 和肿瘤进展的机制，以及确定 TFR 衍生的神经突蛋白促进肿瘤轴突发生的能力。此处获得的调查结果将彻底改变我们对肿瘤神经支配和免疫抑制 TME 的理解，有助于开发新的治疗癌症的免疫治疗方法。