S1P receptors shape immune cell plasticity in colorectal carcinoma

结直肠癌（CRC）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处于极化激活状态，限制或支持肿瘤生长。淋巴细胞如细胞毒性CD8+ T细胞、th1极化的CD4+ T细胞、记忆T细胞和经典活化的巨噬细胞或中性粒细胞等髓样细胞与患者预后良好相关，而th17极化的CD4+ T细胞和选择性活化的髓样细胞则预示预后不良。用免疫检查点抑制剂重新激活抗肿瘤淋巴细胞作为单药治疗仅在一部分结直肠癌患者中显示出希望。因此，需要在结直肠癌中形成免疫细胞可塑性的新靶点来使肿瘤相关免疫系统向肿瘤排斥分化。基于我们在第一个资助期产生的数据，我们继续研究通过S1P受体1和4的鞘氨醇-1-磷酸（S1P）信号作为CRC免疫细胞可塑性的驱动因素。阻止髓细胞中的S1pr1信号传导限制了小鼠p53缺陷结肠肿瘤的发展，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S1pr1缺失后对肿瘤保护的贡献，从机制上遵循这些观察结果。具体来说，我们分析了S1pr1信号传导对crc相关中性粒细胞表型和功能参数的影响，探讨了肿瘤模型中的中性粒细胞耗竭，并确定了中性粒细胞扩增的机制。在AOM/DSS模型中，删除免疫细胞限制性S1pr4在很大程度上阻止了CRC的生长，没有任何迹象表明初始炎症有限。相反，S1pr4缺失增加了保护性CD8+记忆T细胞浸润。基于crc浸润的CD8+ T细胞的RNA-Seq数据，我们重点分析了I型干扰素信号传导对CD8+记忆T细胞扩增的作用机制。我们的研究将证实第一个资助期的发现，通过提供免疫细胞极化的S1pr1和s1pr4依赖机制，提示S1P信号在CRC发展中是一个重要的决定因素。

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.