Atypical chemokine receptors in cancer: friends or foes?

Abstract

The chemokine system is a fundamental component of cancer-related inflammation involved in all stages of cancer development. It controls not only leukocyte infiltration in primary tumors but also angiogenesis, cancer cell proliferation, and migration to metastatic sites. Atypical chemokine receptors are a new, emerging class of regulators of the chemokine system. They control chemokine bioavailability by scavenging, transporting, or storing chemokines. They can also regulate the activity of canonical chemokine receptors with which they share the ligands by forming heterodimers or by modulating their expression levels or signaling activity. Here, we summarize recent results about the role of these receptors (atypical chemokine receptor 1/Duffy antigen receptor for chemokine, atypical chemokine receptor 2/D6, atypical chemokine receptor 3/CXC-chemokine receptor 7, and atypical chemokine receptor 4/CC-chemokine receptor-like 1) on the tumorigenesis process, indicating that their effects are strictly dependent on the cell type on which they are expressed and on their coexpression with other chemokine receptors. Indeed, atypical chemokine receptors inhibit tumor growth and progression through their activity as negative regulators of chemokine bioavailability, whereas, on the contrary, they can promote tumorigenesis when they regulate the signaling of other chemokine receptors, such as CXC-chemokine receptor 4. Thus, atypical chemokine receptors are key components of the regulatory network of inflammation and immunity in cancer and may have a major effect on anti-inflammatory and immunotherapeutic strategies.

Proinflammatory CX3CR1+CD59+Tumor Necrosis Factor–Like Molecule 1A+Interleukin‐23+ Monocytes Are Expanded in Patients With Ankylosing Spondylitis and Modulate Innate Lymphoid Cell 3 Immune Functions

“…[6] D6 is a decoy and scavenger receptor for most inflammatory CC chemokines, including CCL2, and helps prevent tissue inflammatory reactions. [7] Mice lacking D6 expression in the nonhematopoietic compartment display a significant increase of pro-inflammatory monocytes in the peripheral blood and in secondary lymphoid tissues in a CCR2-dependent manner. [6] Thus the net CX3CR1 mediated immune response likely is affected by the balancing effects of CCL2 and D6.…”

The long pentraxin PTX3: A prototypical sensor of tissue injury and a regulator of homeostasis

“…Evidence of a non‐redundant role of inflammatory CC chemokine in carcinogenesis have been provided by analysing the involvement of atypical chemokine receptor, such as D6. D6 acts as decoy receptor, preventing worsened chemokine signaling during inflammatory response and mice lacking D6 expression have an increased inflammation‐related cancer …”

“…D6 acts as decoy receptor, preventing worsened chemokine signaling during inflammatory response and mice lacking D6 expression have an increased inflammation-related cancer. 182,183…”

Mechanisms of Regulation of the Chemokine-Receptor Network

“…Notably, atypical chemokine receptors tend to display high ligand promiscuity (Figure 2). Thus, the main function of ACKRs is thought to be regulation of the innate and adaptive immune response by acting as a chemokine reservoir or scavenger [76,77,78,79,80,81]. This role has been demonstrated both in vitro and in vivo for ACKR2/D6, the first receptor to be functionally classified as an atypical chemokine receptor [82,83].…”