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

在一些研究中，适应性免疫系统细胞浸润结直肠癌与总体和无进展生存期的改善有关。然而，解释CRC适应性免疫反应个体差异的分子机制尚不清楚。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T滤泡辅助细胞（Tfh）细胞和B细胞表达）在CRC的适应性免疫应答中发挥重要作用。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预后相关。然而，到目前为止，这些观察结果的分子机制和功能相关性尚未得到评估。在本项目中，我们将分析与人类CRC相关的小鼠CRC模型（AOM， AOM+DSS和非转移/转移类器官模型）中CXCL13-CXCR5信号传导的各个方面。通过CXCL13缺陷CRC类器官和CXCL13缺陷CD4+ T细胞过继转移实验，我们将评估CRC细胞或肿瘤浸润CD4+ T细胞表达CXCL13对Tfh和B细胞浸润肿瘤及异位淋巴样结构形成的影响。通过在Rag1-/-小鼠中应用不同的过继转移策略，我们将表征CXCL13信号在T细胞或B细胞中的功能相关性，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适应性免疫反应调控的认识，可能为受影响的患者提供新的治疗策略。

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.