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

项目摘要 最近的研究强调了浸润肿瘤微环境（TME）的神经在肿瘤微环境中的重要作用。 肿瘤发生和癌症进展。目前在这一领域的研究主要集中在影响 自主神经系统功能障碍或心理应激诱导的激素网络对恶性肿瘤的影响 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，尚未被广泛研究。本提案的总体目标是 定义一个特定的Treg亚群，称为滤泡调节性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，这是癌症研究领域中未探索的领域。我们 最近报道了TFR细胞的促肿瘤活性，这取决于转录因子的表达。 因子Blimp 1（由Prdm 1编码）。进一步的分析显示，较高的肿瘤TFR标记沿着 PRDM 1表达表明在许多癌症中恶性度和转移风险增加。此外，委员会认为， 与常规Treg细胞及其外周对应物相比，肿瘤内TFR细胞表达更高， neuritin（由Nrn 1编码）是一种与肿瘤发生有关的神经营养因子， 行动大体上仍不明朗。值得注意的是，TFR签名和PRDM 1与NRN 1表达正相关 在癌症患者中。由于Foxp 3特异性缺失而破坏TFR抑制的小鼠中的肿瘤内TFR细胞 Blimp 1的表达显著降低。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细胞的肿瘤具有显著减少的神经丝积聚，并且 肿瘤内TFR细胞富含与轴突发生有关的基因标记。我们建议将 TFR细胞利用Blimp 1-neuritin轴调节TME和肿瘤进展的机制，以及 以确定TFR衍生的神经突素在肿瘤中促进轴突生成的能力。在此获得的结果将 彻底改变我们对肿瘤神经支配和免疫抑制TME的理解，帮助开发新的 免疫疗法来治疗癌症。

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.