The CXCL13-CXCR5 pathway as a regulator of adaptive immunity in colorectal cancer

CXCL13-CXCR5 通路作为结直肠癌适应性免疫的调节因子

• 批准号: 428370716
• 负责人: Professor Dr. Maximilian Waldner, Ph.D.
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/428370716?language=en
• 关键词: CXCL13; CXCR5; pathway; regulator; adaptive

The infiltration of CRC with cells of the adaptive immune system has been associated with an improved course of disease regarding overall and progression free survival in several studies. However, molecular mechanisms explaining the individual differences of the adaptive immune response against CRC are only poorly understood. Growing evidence including our own preliminary data proposes an important role for the chemokine CXCL13 and its receptor CXCR5, which is mainly expressed by T follicular helper (Tfh) cells and B cells, as regulators of the adaptive immune response against CRC. For instance, a deletion of CXCL13 in cancer cells of human CRC correlates with worse prognosis, whereas the infiltration of CRC tissue with CXCL13 expressing T cells is associated with a favorable outcome. However, molecular mechanisms and the functional relevance of these observations have not been evaluated so far. Within this project we will analyze various aspects of CXCL13-CXCR5 signaling in mouse models of CRC (AOM, AOM+DSS and a non-metastatic/metastatic organoid model) in correlation with human CRC. Using CXCL13-deficient CRC organoids and adoptive transfer experiments with CXCL13-deficient CD4+ T cells, we will evaluate the effect of CXCL13 expressed by CRC cells or tumor infiltrating CD4+ T cells on tumor infiltration with Tfh and B cells and the formation of ectopic lymphoid structures. Through the application of different adoptive transfer strategies into Rag1-/- mice, we will characterize the functional relevance of CXCL13 signaling in T cells or B cells and the subsequent effects on cytotoxic T cell responses, B cell activation and B cell class switch.Altogether, our data will help to improve our knowledge about the regulation of the adaptive immune response against CRC, potentially providing new therapeutic strategies for affected patients.

在多项研究中，适应性免疫系统细胞对结直肠癌的浸润与总体生存期和无进展生存期的改善有关。然而，人们对CRC适应性免疫反应个体差异的分子机制知之甚少。包括我们自己的初步数据在内的越来越多的证据表明，趋化因子 CXCL13 及其受体 CXCR5（主要由滤泡辅助 T (Tfh) 细胞和 B 细胞表达）作为针对 CRC 的适应性免疫反应的调节剂发挥着重要作用。例如，人类结直肠癌癌细胞中CXCL13的缺失与较差的预后相关，而表达CXCL13的T细胞浸润结直肠癌组织则与良好的结果相关。然而，迄今为止，这些观察结果的分子机制和功能相关性尚未得到评估。在该项目中，我们将分析 CRC 小鼠模型（AOM、AOM+DSS 和非转移/转移性类器官模型）中与人类 CRC 相关的 CXCL13-CXCR5 信号传导的各个方面。利用CXCL13缺陷型CRC类器官和CXCL13缺陷型CD4+ T细胞的过继转移实验，我们将评估CRC细胞或肿瘤浸润CD4+ T细胞表达的CXCL13对Tfh和B细胞肿瘤浸润以及异位淋巴结构形成的影响。通过在 Rag1-/- 小鼠中应用不同的过继转移策略，我们将表征 T 细胞或 B 细胞中 CXCL13 信号传导的功能相关性，以及随后对细胞毒性 T 细胞反应、B 细胞激活和 B 细胞类别转换的影响。总之，我们的数据将有助于提高我们对 CRC 适应性免疫反应调节的了解，有可能为受影响的患者提供新的治疗策略。