S1P receptors shape immune cell plasticity in colorectal carcinoma

S1P受体塑造结直肠癌免疫细胞可塑性

• 批准号: 428359092
• 负责人: Professor Dr. Bernhard Brüne
• 金额: --
• 依托单位: Institut für Biochemie I: Pathobiochemie
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/428359092?language=en
• 关键词: S1P; receptors; shape; immune; cell

Composition and quality of the tumor-associated immune system in colorectal cancer (CRC) emerged in having both predictive and therapeutic value. Both, lymphocytes and myeloid cells occur in polarized activation states that either restrict or support tumor growth. Lymphocytes such as cytotoxic CD8+ T cells, TH1-polarized CD4+ T cells, memory T cells and myeloid cells such as classically activated macrophages or neutrophils are associated with good patient prognosis, whereas TH17-polarized CD4+ T cells and alternatively activated myeloid cells indicate bad prognosis. Re-activation of anti-tumor lymphocytes with immune checkpoint inhibitors as monotherapy has shown promise in only a subset of CRC patients. Therefore, new targets that shape immune cell plasticity in CRC are needed to polarize the tumor-associated immune system towards tumor rejection. Based on our data generated during the first funding period, we continue investigating sphingosine-1-phosphate (S1P) signaling through S1P receptors 1 and 4 as a driver of immune cell plasticity in CRC. Preventing S1pr1 signaling in myeloid cells restricted development of p53-deficient colorectal tumors in mice, associated with an increase in tumor-associated neutrophils. We follow these observations mechanistically by investigating the contribution of neutrophils to tumor protection upon S1pr1 deletion. Specifically, we analyze the impact of S1pr1 signaling on phenotypic and functional parameters of CRC-associated neutrophils, approach neutrophil depletion in tumor models, and identify mechanisms to explain neutrophil expansion. Deletion of the immune cell-restricted S1pr4 largely prevented CRC growth in the AOM/DSS model without any indication of limited initial inflammation. Rather, S1pr4 deletion, increased protective CD8+ memory T cell infiltrates. Based on RNA-Seq data from CRC-infiltrating CD8+ T cells, we focus on mechanistic analyses towards the contribution of type I interferon signaling to CD8+ memory T cell expansion. Our studies will substantiate findings of the first funding period, suggesting S1P signaling as an important determinant in CRC development by providing S1pr1 and S1pr4-dependent mechanisms of immune cell polarization.

结直肠癌（CRC）中肿瘤相关免疫系统的组成和质量具有预测和治疗价值。淋巴细胞和骨髓细胞都以极化激活状态发生，这限制或支持肿瘤生长。淋巴细胞如细胞毒性CD 8 + T细胞、TH 1极化的CD 4 + T细胞、记忆T细胞和骨髓细胞如经典活化的巨噬细胞或嗜中性粒细胞与良好的患者预后相关，而TH 17极化的CD 4 + T细胞和替代活化的骨髓细胞指示不良预后。用免疫检查点抑制剂作为单一疗法重新激活抗肿瘤淋巴细胞仅在一部分CRC患者中显示出前景。因此，需要在CRC中塑造免疫细胞可塑性的新靶标来使肿瘤相关免疫系统朝向肿瘤排斥反应。基于我们在第一个资助期内产生的数据，我们继续研究通过S1 P受体1和4的鞘氨醇-1-磷酸（S1 P）信号传导作为CRC免疫细胞可塑性的驱动因素。阻止骨髓细胞中的S1 pr 1信号传导限制了小鼠中p53缺陷型结直肠肿瘤的发展，与肿瘤相关中性粒细胞的增加有关。我们通过研究中性粒细胞在S1 pr 1缺失后对肿瘤保护作用的贡献，机械地跟踪这些观察结果。具体来说，我们分析了S1 pr 1信号对CRC相关中性粒细胞表型和功能参数的影响，在肿瘤模型中接近中性粒细胞耗竭，并确定了解释中性粒细胞扩增的机制。在AOM/DSS模型中，免疫细胞限制性S1 pr 4的缺失在很大程度上阻止了CRC的生长，而没有任何有限的初始炎症迹象。相反，S1 pr 4缺失增加了保护性CD 8+记忆T细胞浸润。基于来自CRC浸润性CD 8 + T细胞的RNA-Seq数据，我们专注于对I型干扰素信号传导对CD 8+记忆T细胞扩增的贡献的机制分析。我们的研究将证实第一个资助期的发现，表明S1 P信号通过提供免疫细胞极化的S1 pr 1和S1 pr 4依赖性机制作为CRC发展的重要决定因素。