CXCR4/CXCL12 Activities in the Tumor Microenvironment and Implications for Tumor Immunotherapy

Simple Summary Chemokines are small soluble proteins that control and regulate cell trafficking within and between tissues by binding to their receptors. Among them, CXCL12 and its receptor CXCR4 appeared with ancestral vertebrates, are expressed almost ubiquitously, and play essential roles in embryogenesis and organogenesis. In addition, CXCL12 and CXCR4 are involved in antigen recognition by T and B cells and in shaping the tumor microenvironment (TME), mainly towards dampening immune responses. New data indicate that CXCR4 interacts with the surface protein CD47 in a novel form of immunosurveillance, called ImmunoGenic Surrender (IGS). Following the co-internalization of CXCR4 and CD47 in tumor cells, macrophages phagocytose them and cross-present their antigens to the adaptive immune system, leading to tumor rejection in a fraction of mice. All of these specific activities of CXCL12 and CXCR4 in antigen presentation might be complementary to current immunotherapies. CXCR4 is a G-Protein coupled receptor that is expressed nearly ubiquitously and is known to control cell migration via its interaction with CXCL12, the most ancient chemokine. The functions of CXCR4/CXCL12 extend beyond cell migration and involve the recognition and disposal of unhealthy or tumor cells. The CXCR4/CXCL12 axis plays a relevant role in shaping the tumor microenvironment (TME), mainly towards dampening immune responses. Notably, CXCR4/CXCL12 cross-signal via the T and B cell receptors (TCR and BCR) and co-internalize with CD47, promoting tumor cell phagocytosis by macrophages in an anti-tumor immune process called ImmunoGenic Surrender (IGS). These specific activities in shaping the immune response might be exploited to improve current immunotherapies.