Atypical chemokine receptors in cancer

Atypical chemokine receptors (ACKRs) are a group of seven-transmembrane spanning serpentine receptors that are structurally homologous to classical G-protein-coupled receptors and bind cognate chemokines with high affinities but do not signal via G-proteins or mediate cell migration. However, ACKRs efficiently modify the availability and function of chemokines in defined microanatomical environments, can signal via intracellular effectors other than G-proteins, and play complex roles in physiology and disease, including in cancer. In this review, we summarize the findings on the diverse contributions of individual ACKRs to cancer development, progression, and tumor-host interactions. We discuss how changes in ACKR expression within tumor affect cancer growth, tumor vascularization, leukocyte infiltration, and metastasis formation, ultimately resulting in differential disease outcomes. Across many studies, ACKR3 expression was shown to support tumor growth and dissemination, whereas ACKR1, ACKR2, and ACKR4 in tumors were more likely to contribute to tumor suppression. With few notable exceptions, the insights on molecular and cellular mechanisms of ACKRs activities in cancer remain sparse, and the intricacies of their involvement are not fully appreciated. This is particularly true for ACKR1, ACKR2 and ACKR4. A better understanding of how ACKR expression and functions impact cancer should pave the way for their future targeting by new and effective therapies.