CXCL13 and Its Receptor CXCR5 in Cancer: Inflammation, Immune Response, and Beyond

Abstract

It is well-established that the chemokine C-X-C motif ligand 13 (CXCL13) and its receptor, the G-protein coupled receptor (GPCR) CXCR5, play fundamental roles in inflammatory, infectious and immune responses. Originally identified as a B-cell chemoattractant, CXCL13 exerts important functions in lymphoid neogenesis, and has been widely implicated in the pathogenesis of a number of autoimmune diseases and inflammatory conditions, as well as in lymphoproliferative disorders. Current evidence also indicates that the CXCL13:CXCR5 axis orchestrates cell-cell interactions that regulate lymphocyte infiltration within the tumor microenvironment, thereby determining responsiveness to cytotoxic and immune-targeted therapies. In this review, we provide a comprehensive perspective of the involvement of CXCL13 and its receptor in cancer progression. Studies in recent years postulated novel roles for this chemokine in controlling the cancer cell phenotype, and suggest important functions in the growth and metastatic dissemination of solid tumors. Carcinogens have been found to induce CXCL13 production, and production of this chemokine within the tumor milieu has been shown to impact the proliferation, migration, and invasive properties of cancer cells. Thus, the complex networks of cellular interactions involving tumoral CXCL13 and CXCR5 integrate to promote cancer cell autonomous and non-autonomous responses, highlighting the relevance of autocrine and paracrine interactions in dictating the cancer phenotype. Dissecting the molecular and signaling events regulated by CXCL13 and how this chemokine dynamically controls the interaction between the cancer cell and the tumor microenvironment is key to identify novel effectors and therapeutic targets for cancer treatment.

Keywords: CXCL13; CXCR5; cancer progression; immune responses; inflammation.

Figure 1

Activation of signaling pathways by CXCL13. The chemokine CXCL13 binds specifically to the GPCR CXCR5. Upon activation, CXCR5 couples to the activation of pathways implicated in cell survival, proliferation, and migration, therefore impacting on the tumorigenic and metastatic activity of cancer cells.

Figure 2

Major functions of CXCL13 in immune responses, inflammation, and lymphoproliferative diseases. The chemokine CXCL13 has been identified as a major regulator of immune responses and plays key roles in the pathophysiology of inflammatory, infectious, and lymphoproliferative diseases. In addition, emerging evidence identified CXCL13 as a biomarker for cancer progression and response to therapy.

Figure 3

CXCL13 and the formation of tertiary lymphoid structures. (A) Cytokines play key roles in the immunomodulation of both T helper type-1 (cellular immunity) or T helper type-2 responses (humoral immunity). The shift from an immunological pattern with a T helper type-1 orientation to a T helper type-2 pattern mediated by cytokines is a key event in tumorigenesis. (B) CXCL13 produced by T-cells plays a fundamental role in the formation of tumor-associated tertiary lymphoid structures and germinal center orchestration: tumor infiltrating T-cells are recruited into the tumor site by transendothelial migration via high endothelial venules mediated by chemokine/chemokine receptor interactions. Intra-tumoral infiltration of T_FH cells is a key step in the formation of tertiary lymphoid structures, thus generating and promoting B-cell responses in the germinal center (i.e., local memory B cell differentiation, as well as with the expansion of a subpopulation of T regulatory cells).

Figure 4

The CXCL13:CXCR5 axis is a key element in B-cell and tumor cell responses. The chemokine CXCL13, acting on the GPCR CXCR5, promotes chemotaxis, germinal center formation, and the differentiation to plasma cells and B-memory lymphocytes. CXCL13 also target cancer cells to promote proliferation, migration, and invasion. These effects vary depending on the cancer type, which may express different levels of CXCR5.

Figure 5

CXCL13 in prostate cancer. In prostate tumors, CXCL13 can be produced both by cancer cells as well as by cells in the tumor microenvironment, such as myofibroblasts. In prostate cancer cells, up-regulation of the kinase PKCε and loss of the tumor suppressor Pten (which leads to elevated PI3K activity) lead to the activation of the non-canonical NF-κB pathway, and transcriptionally activate the CXCL13 gene. CXCL13 produced in this autocrine manner, together with CXCL13 generated by stromal cells, may significantly impact on the tumorigenic and metastatic phenotypes of androgen-independent prostate cancer cells.