Given the crucial role of CXCL13/CXCR5 signaling in B cell migration and TLS formation, a further understanding of how these processes are regulated by the CXCL13/CXCR5 axis might provide a novel strategy to enhance the response to immune checkpoint blockade therapy. == 7. the CXCL13/CXCR5 axis in tumor tissue and the TME is required to design an efficient immune-based therapy. In this review, we summarize the molecular events and TME alterations caused by CXCL13/CXCR5 and briefly discuss the potentials of brokers targeting this axis in different malignant tumors. Keywords:C-X-C chemokine ligand 13 (CXCL13), C-X-C chemokine receptor type 5 (CXCR5), malignancy, tumor microenvironment == 1. Introduction == Chemokines are a family of chemotactic cytokines with small molecular weights (814 kDa) [1]. Chemokines are classified into four groups according to the position of the first two cysteines closest to the amino terminus: C, CC, CXC, and CX3C [2]. Chemokines exert their functions by binding to their receptors, which are seven-transmembrane guanine-protein-coupled receptors (GPCRs) [3]. Chemokines have important functions in regulating lymphoid tissue development, immune homeostasis, and inflammatory responses by directing the migration of leukocytes into the hurt or infected tissues [2]. A complex chemokine-chemokine receptor signaling network is critical to the tumor microenvironment (TME), which makes pivotal BI-9627 contributions to tumor cell proliferation, migration, invasion, angiogenesis, and evasion of anti-tumor immunity, facilitating tumor initiation, progression, and metastasis [4,5,6,7,8]. Chemokines and their receptors also modulate lymphocyte populations in the TME, thus inducing resistance to immune checkpoint inhibitors that exhibit remarkable efficacies on a proportion of patients with many malignancy types [9,10]. Inconsistent with these observations, targeting chemokine receptors with neutralizing antibodies endow a more sensitized phenotype and enhance responses to immune checkpoint blockades [11,12]. == 2. CXCL13/CXCR5 and Immune Homeostasis == == 2.1. Rabbit polyclonal to FN1 CXCL13/CXCR5: Genes and Proteins == C-X-C chemokine ligand 13 (CXCL13), also known as B-cell bringing in chemokine 1 (BCA-1) or B-lymphocyte chemoattractant (BLC), was originally identified as a homeostatic chemokine to attract B cells, a minority of T cells, and macrophages [13]. The humanCXCL13gene localizes on chromosome 4q21 and BI-9627 encodes CXCL13 protein, which has 109 amino acids, a molecular mass of 12,664 Da, and a crystal structure as below (Physique 1A). The receptor of CXCL13 is the C-X-C chemokine receptor type 5 (CXCR5), which is also named Burkitts lymphoma receptor 1 (BLR1) and is defined as a member of the superfamily of seven-transmembrane GPCRs (Physique 1B). CXCR5 has two transcripts, both localized around the cell membrane [14], and is expressed by follicular helper T cells (Tfh) [15], circulating CD4+T cells [16], B cells [17], CD68+macrophages [18], and tumor cells. Moreover, FANCA-mediated CXCR5 neddylation is usually involved in targeting the receptor to the cell membrane, and CXCR5 neddylation stimulates cell migration and motility [19]. == Physique BI-9627 1. == Crystal structure of CXCL13 and CXCR5. (A). Illustration of the CXCL13 monomer (UniProKB-O43927) showing domain hits with deep coloration. (B). Illustration of the CXCR5 monomer (UniProKB-P32302) showing seven transmembrane helixes and domain name hits (deeply colored). Structural models were obtained from SWISS-MODEL (http://swissmodel.expasy.org/repository/. utilized on 15 April 2021). == 2.2. CXCL13/CXCR5 Axis == The precise mechanism of how the CXCR5 receptor responds to CXCL13 and mediates signaling activation has not been fully elucidated. Evidence has exhibited that CXCR5 interacts with cytosolic and membrane proteins to form heterodimers and heterotrimers, BI-9627 respectively [20,21,22]. CXCR5 couples to cytosolic , , and subunits of G proteins to form heterotrimeric guanine nucleotide-binding proteins [20]. After CXCL13 binds to CXCR5, G proteins dissociate from CXCR5, dividing into Gand G, which stimulate different downstream molecules and subsequently trigger specific intracellular transmission transduction pathways [20,23]. The intracellular domains, and probably the transmembrane-spanning domains of CXCR5, are required to activate G proteins [24,25]. CXCR5 can also form heterodimers with membrane proteins, such as CXCR4 and EpsteinBarr virus-induced receptor 2 (EBI2) [20,22]. The EBI2/CXCR5 heterodimer lowers the affinity of CXCL13 for CXCR5 and reduces the activation of G proteins, potentially contributing to the alteration of the CXCR5 binding pocket by heterodimer formation [22]. == 2.3. Physiological Functions of CXCL13/CXCR5 == CXCL13 is usually abundantly expressed on follicular helper T cells (Tfh), follicular dendritic cells (FDCs), and stromal cells in the follicles of secondary lymphoid organs (SLOs) and is essential for the development of the B cell zones of SLOs [13,26,27,28]. SLOs, which include the spleen, lymph nodes, and Peyers patches, coordinate antigen-specific main immune responses via promoting the interactions between antigen-presenting cells and lymphocytes. CXCR5 is expressed by mature B lymphocytes [29], a subpopulation of follicular.