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

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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.