Potential Role of CXCL13/CXCR5 Signaling in Immune Checkpoint Inhibitor Treatment in Cancer

SIMPLE SUMMARY: Immunotherapy is currently the backbone of new drug treatments for many cancer patients. CXC chemokine ligand 13 (CXCL13) is an important factor involved in recruiting immune cells that express CXC chemokine receptor type 5 (CXCR5) in the tumor microenvironment and serves as a key molecular determinant of tertiary lymphoid structure (TLS) formation. An increasing number of studies have identified the influence of CXCL13 on prognosis in patients with cancer, regardless of the use of immunotherapy treatment. However, no comprehensive reviews of the role of CXCL13 in cancer immunotherapy have been published to date. This review aims to provide an overview of the CXCL13/CXCR5 signaling axis to summarize its mechanisms of action in cancer cells and lymphocytes, in addition to effects on immunity and cancer pathobiology, and its potential as a biomarker for the response to cancer immunotherapy. ABSTRACT: Immune checkpoint inhibitors (ICIs), including antibodies that target programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA4), represent some of the most important breakthroughs in new drug development for oncology therapy from the past decade. CXC chemokine ligand 13 (CXCL13) exclusively binds CXC chemokine receptor type 5 (CXCR5), which plays a critical role in immune cell recruitment and activation and the regulation of the adaptive immune response. CXCL13 is a key molecular determinant of the formation of tertiary lymphoid structures (TLSs), which are organized aggregates of T, B, and dendritic cells that participate in the adaptive antitumor immune response. CXCL13 may also serve as a prognostic and predictive factor, and the role played by CXCL13 in some ICI-responsive tumor types has gained intense interest. This review discusses how CXCL13/CXCR5 signaling modulates cancer and immune cells to promote lymphocyte infiltration, activation by tumor antigens, and differentiation to increase the antitumor immune response. We also summarize recent preclinical and clinical evidence regarding the ICI-therapeutic implications of targeting the CXCL13/CXCR5 axis and discuss the potential role of this signaling pathway in cancer immunotherapy.