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.

The Genomic Architecture of Circulating Cytokine Levels Points to Drug Targets for Immune-Related Diseases

“…25,26 By acting as scavenger receptor, ACKR1 modulates the bioavailability of cytokines and thereby affects inflammatory responses. 27,28 The identified associations were driven by rs12075, a well-characterized missense variant in ACKR1, resulting in less efficient chemokine binding to ACKR1 due to loss of a necessary amino-acid sulfation ( Figure 6a ). 29 The impaired receptor binding leads to elevated circulatory levels of chemokines and might in turn result in a compensatory increase in ACKR1 expression which could explain the positive association between genetically proxied ACKR1 and its ligands.…”

Encompassing view of spatial and single-cell RNA-seq renews the role of the microvasculature in human atherosclerosis

“…In agreement with previous studies, we demonstrated the accumulation of lymphocytes in the adventitia 47,48 . However, with the unbiased approach of spatial transcriptomics, we analyzed their potential interactions with adventitial endothelial cells and pericytes and found that the Major Histocompatibility Complex II, which can support the antigen- presentation and facilitate the adaptive immune response 21,49 and the expression of ACKR1, which might be involved in angiogenesis, chemotaxis, and cellular retention signals 50 were higher expressed in adventitial than in luminal endothelium. Notably, pericytes have also been demonstrated as antigen-presenting and cells for T- lymphocytes 43 .…”

Deep phenotyping of the prostate tumor microenvironment reveals molecular stratifiers of relapse linked to inflammatory chemokine expression and aberrant metabolism

“…Considering that our data suggests ACKR1 to be mainly expressed on endothelium in the prostate and the observed increased immune cell infiltration a similar role in the prostate as in the lungs appears plausible. Interestingly, ACKR1's role in cancer has been reported as dominantly protective against tumor metastasis, increased proliferation, and is associated with positive outcomes [35]. Nevertheless, in PCa reduced ACRK1 expression on erythrocytes in men of African descent appeared not to be linked to aggressiveness [36,37] while ACKR1-deficient mice showed increased tumor growth [38].…”