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

在几项研究中，结直肠癌与适应性免疫系统的细胞的渗透与总体和无进展存活率方面的病程改善有关。然而，解释针对CRC的获得性免疫反应的个体差异的分子机制还知之甚少。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作为针对结直肠癌的获得性免疫反应的调节因子，主要由T滤泡辅助细胞(TFH)和B细胞表达。例如，人结直肠癌癌细胞中CXCL13的缺失与较差的预后相关，而结直肠癌组织中表达CXCL13的T细胞的浸润与良好的预后相关。在这个项目中，我们将分析结直肠癌小鼠模型(AOM、AOM+DSS和非转移/转移性器官模型)中CXCL13-CXCR5信号的各个方面与人类结直肠癌的相关性。利用CXCL13缺陷的CRC有机物和CXCL13缺陷的CD4+T细胞的过继转移实验，我们将评估CXCL13表达的CRC细胞或肿瘤浸润性CD4+T细胞对肿瘤与TfH和B细胞的侵袭和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针对CRC的获得性免疫反应调节的了解，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.