Prospects for targeting ACKR1 in cancer and other diseases

Abstract

The chemokine network is comprised of a family of signal proteins that encode messages for cells displaying chemokine G-protein coupled receptors (GPCRs). The diversity of effects on cellular functions, particularly directed migration of different cell types to sites of inflammation, is enabled by different combinations of chemokines activating signal transduction cascades on cells displaying a combination of receptors. These signals can contribute to autoimmune disease or be hijacked in cancer to stimulate cancer progression and metastatic migration. Thus far, three chemokine receptor-targeting drugs have been approved for clinical use: Maraviroc for HIV, Plerixafor for hematopoietic stem cell mobilization, and Mogalizumab for cutaneous T-cell lymphoma. Numerous compounds have been developed to inhibit specific chemokine GPCRs, but the complexity of the chemokine network has precluded more widespread clinical implementation, particularly as anti-neoplastic and anti-metastatic agents. Drugs that block a single signaling axis may be rendered ineffective or cause adverse reactions because each chemokine and receptor often have multiple context-specific functions. The chemokine network is tightly regulated at multiple levels, including by atypical chemokine receptors (ACKRs) that control chemokine gradients independently of G-proteins. ACKRs have numerous functions linked to chemokine immobilization, movement through and within cells, and recruitment of alternate effectors like β-arrestins. Atypical chemokine receptor 1 (ACKR1), previously known as the Duffy antigen receptor for chemokines (DARC), is a key regulator that binds chemokines involved in inflammatory responses and cancer proliferation, angiogenesis, and metastasis. Understanding more about ACKR1 in different diseases and populations may contribute to the development of therapeutic strategies targeting the chemokine network.

Keywords: ACKR1; DARC; cancer; chemokine; inflammation.

Figure 1

ACKR1-4 chemokine interaction network Chemokine ligands described for atypical chemokine receptors ACKR1, ACKR2, ACKR3, and ACKR4. *Chemokines are described as weak binders to ACKR1.

Figure 2

ACKR1 snake plot Atypical chemokine receptor 1 has seven transmembrane domains and multiple binding sites in the extracellular N-terminus. Residue 42 is depicted as aspartic acid corresponding to FyB variant. DBP, Duffy Binding Protein; LukE, Leukocidin E.

Figure 3

ACKR1 and tumor microenvironment Chemokine signaling in the tumor microenvironment is regulated by ACKR1 expression. Left panel describes chemokine effects that promote tumor phenotypes. ACKR1 (black) expression can be diminished on tumor cells or by the Fy^ES polymorphism. Angiogenesis can be triggered by chemokines secreted from TAMs, stromal cells, or by cancer cells themselves via activation of endothelial CXCR2 (red). Cancer cells release numerous chemokines, including CCL2, CCL5, CXCL8, and others that can act to suppress anti-tumor immunity. Various cancer types express a panel of CKRs (blue) including CCR1, CCR2, CXCR2, CXCR4, and others that support tumor proliferation and metastasis. Primary tumors can silence expression of chemokines like CXCL12 and increase expression of CKRs like CXCR4 to promote metastasis. Right panel shows proposed mechanisms of ACKR1 regulation. ACKR1 receptors on erythrocytes can act as a sink to buffer chemokine levels and may have interactions with ACKR1 expressed on endothelial cells. ACKR1 enrichment at endothelial junctions promotes neutrophil diapedesis via CXCL1 and CXCL2 exchange, and increased endothelial ACKR1 improves recruitment of macrophages, CD4+ and CD8+ T-cells. Expression of ACKR1 in cancer models or patient tumor samples has been shown to modulate CCL2 and CXCL8, ligands of CCR2, CCR4, and CXCR2. ACKR1 modulates many chemokines and regulation of multiple CKRs may contribute to the improved clinical outcomes observed. TAM, Tumor associated macrophage; MDSC, Myeloid-derived suppressor cell; Fy^ES RBC, “Erythroid-silent” erythrocyte; CKR, chemokine receptor.