Elucidating the role of the CXCL13/CXCR5 signaling axis in Angioimmunoblastic T-Cell Lymphoma (AITL)

项目总结/文摘

Project Summary/Abstract Angioimmunoblastic T-Cell Lymphoma (AITL) is a rare type of non-Hodgkin lymphoma (NHL). To date, there are no targeted therapies for the cancer, which is reflected in a dismal five-year overall survival rate at around 30% following conventional chemotherapeutic regimens. Clinicopathological analysis of affected individuals has revealed that a member of the chemokine family—CXCL13—is consistently upregulated in neoplastic tissues, and it is now used as a diagnostic marker for the disease. The cognate receptor for CXCL13, CXCR5, is a G protein-coupled receptor (GPCR) that is expressed on B lymphocytes as well as a small subset of CD4+ T lymphocytes known as Follicular Helper T cells (TFH). TFH cells are believed to be the neoplastic cell of origin in AITL, as the gene signature of AITL has been shown to be enriched in genes that are markers for these cells, including CXCL13. This chemokine is necessary for B cell recruitment into germinal centers and for B cell activation in a normal physiological setting. In AITL, there is indication that aberrant expression of CXCL13 may activate an autocrine feedback loop by binding to CXCR5 on TFH cells, possibly contributing to their proliferation and survival; CXCL13 is also thought to cause B cell activation in the cancer, leading to their secretion of effector molecules that cause Follicular Dendritic Cell (FDC) proliferation and invasion into the tumorous tissues. FDCs are then thought to intimately associate with T cells in the tumor, promoting the TFH phenotype. These autocrine and positive feedback loops could be blocked by antagonism of the CXCL13/CXCR5 signaling axis. Our lab believes that blockade of CXCR5 may serve as an effective targeted therapeutic for patients with AITL. A mouse model of AITL is available for use in basic research—these mice exhibit a point mutation in an mRNA-binding protein known as Roquin. Heterozygosity for this so-called “sanroque” mutation (i.e., Roquinsan/+ genotype) causes mice to develop tumors that display histologic features diagnostic of AITL. We propose to discern CXCR5's role in disease pathogenesis and use as a therapeutic target for the disease. The two aims of this proposal are: 1. Develop a CXCR5 antagonist biotherapeutic for in vivo studies in Roquinsan/+ mice via N- terminal modification of CXCL13, a common technique to convert chemokines from agonists into antagonists; 2. Generate and characterize a CD4 promoter-driven inducible CXCR5 knockout in the Roquinsan/+ background. These studies will provide a formal understanding of the role that the CXCL13/CXCR5 axis plays in AITL, and may serve as a proof-of-principle for development of a biotherapeutic targeting CXCR5 in humans for use in the clinic.