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

Abstract

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.

Keywords: ACKR3; BCR; CD47; CXCL12; CXCR4; ImmunoGenic Surrender; TCR; immunotherapy.

Figure 1

CXCR4 membrane interactors and CXCL12-activated signal transduction pathways. (A) CXCL12 binding to CXCR4 leads to the activation of G protein-dependent signaling, MAPK, PI3K and PLC pathways, resulting in diverse biological outcomes such as calcium mobilization, cell proliferation, differentiation, migration and adhesion. CXCR4 can form a heterodimer with ACKR3 (CXCR7), which contributes to modulate CXCL12/CXCR4 signaling. ACKR3 impairs CXCR4-mediated G-protein activation and calcium responses. (B) In T cells, CXCR4 interacts with CD3/TCR. The activation of CXCR4 by CXCL12 induces the formation of the immunological synapsis with antigen presenting cells (APCs) and the activation of the RAS-ERK pathway. The interaction of the TCR with CXCR4 causes the phosphorylation of CXCR4-S339, which leads to PREX-Rac1 activation and to cytokine synthesis and secretion. (C) CXCR4 and CD47 are in contact in cancer cells; the binding to CXCR4 of CXCL12 or BoxA, a truncated form of HMGB1, promotes co-internalization of CXCR4-CD47. Reduction of surface CD47 impairs its recognition by SIRPα, allowing tumor cell phagocytosis by macrophages.

Figure 2

CXCL12 induces the internalization of the CXCR4-CD47 complex. CXCR4 and CD47 are in physical contact on the surface of untreated tumor cells (AB1-B/c-LUC mesothelioma cells, stained green with phalloidin; CXCR4-CD47 Proximity Ligation Assay signal, red). Overnight treatment with CXCL12 causes the almost complete disappearance of the CXCR4-CD47 signal from the cell surface. See [75] for details.