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

• 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
• 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

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.

项目摘要 最近的研究强调了神经渗透到肿瘤微环境（TME）中的重要作用。 肿瘤发生和罐头进展。该领域的当前研究主要集中在 自主神经系统或心理压力引起的激素网络的功能障碍 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，尚未得到广泛的研究。该提议的总体目标是 定义特定的Treg子集（称为卵泡调节T（TFR）细胞）如何调节TME以促进癌症 通过产生和利用神经营养因子，这是癌症研究领域未开发的领域。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）。进一步的分析表明，较高的肿瘤TFR签名以及 PRDM1表达表明许多癌症的恶性肿瘤和转移风险增加。而且， 与常规的Treg细胞及其外周相比，肿瘤内TFR细胞表达较高 神经蛋白水平（由NRN1编码），一种与肿瘤发生有关的神经营养因子 行动仍然在很大程度上不清楚。值得注意的是，TFR签名和PRDM1与NRN1表达呈正相关 在癌症患者中。由于FOXP3特异性缺失而导致TFR抑制的小鼠中肿瘤内TFR细胞 Blimp1的神经素表达大大降低。最重要的是，这些小鼠和小鼠的肿瘤 与野生型肿瘤相比，缺乏TFR细胞显着降低了神经丝的积累，并且 肿瘤内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-神经蛋白轴调节TME和肿瘤进展的机制，并且 定义TFR衍生的神经素在促进肿瘤中的轴突发生方面的能力。这里获得的发现将 彻底改变了我们对肿瘤神经和免疫抑制TME的理解，有助于开发新的 治疗癌症的免疫治疗方法。