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Review
. 2024 Jul 23;25(15):8007.
doi: 10.3390/ijms25158007.

Fractalkine in Health and Disease

Claudia Rodriguez  1 , Luisa Chocarro  1 , Miriam Echaide  1 , Karina Ausin  1 , David Escors  1 , Grazyna Kochan  1
Affiliations
Review

Fractalkine in Health and Disease

Claudia Rodriguez et al. Int J Mol Sci. .

Abstract

CX3CL1 is one of the 50 up-to-date identified and characterized chemokines. While other chemokines are produced as small, secreted proteins, CX3CL1 (fractalkine) is synthetized as a transmembrane protein which also leads to a soluble form produced as a result of proteolytic cleavage. The membrane-bound protein and the soluble forms exhibit different biological functions. While the role of the fractalkine/CX3CR1 signaling axis was described in the nervous system and was also related to the migration of leukocytes to sites of inflammation, its actions are controversial in cancer progression and anti-tumor immunity. In the present review, we first describe the known biology of fractalkine concerning its action through its cognate receptor, but also its role in the activation of different integrins. The second part of this review is dedicated to its role in cancer where we discuss its role in anti-cancer or procarcinogenic activities.

Keywords: FKN; Neurotactin; PD-1; PD-L1; T-cell; dendritic cell; immune checkpoint; immunotherapy.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
FKN polypeptides. Membrane-bound fractalkine can be shed by different proteases resulting in soluble forms. (a) Arrows show sites of proteolytic digestion and the proteases responsible for it. ADAM10, ADAM17, and CatS (blue); MMP2 (red); and secretases α, β, and γ (orange). Below the FKN full-length (FL) molecule, the collection of polypeptides generated via proteolytic cleavages are shown. The first and last amino acid residues are marked. (b) Function of FKN. The membrane-bound form (in blue) causes adhesion of leucocytes to the endothelial surface. It is also responsible for neuron–microglia crosstalk and survival (1). The soluble form (in blue) acts as chemoattractant for different cells which express its receptor CX3CR1 on their surface. Interaction with its receptor results in a signaling cascade (among others, integrin activation and inside-out activation mechanism, shown as colored serrated arrows). (2) Soluble fractalkine in the absence of its receptor CX3CR1 can bind to integrins in their inactive form (binding to the alternative site 2) and activate them (outside-in activation, shown as colored serrated arrows) that is followed by binding to their corresponding ligands (3).
Figure 2
Figure 2
PDB structure of chemokine domain of FKN (PDB 1f2l). The chemokine domain of FKN in the crystal showed a quaternary arrangement [28]. In the figure, four FKN molecules are visible and are indicated in different colors. Nevertheless, FKN does not form oligomers in solution. However, it cannot be disregarded that, in the presence of other molecules, it may oligomerize.
Figure 3
Figure 3
FKN in cancer immunotherapy. (a) Top: cancer cells (black) express PD-L1 on their surface that binds PD-L1 on the surface to T cells (blue cell on the left). This interaction inhibits T cell effector activities and creates a signaling barrier that protects cancer cells from interferon-induced apoptosis. Bottom: anti-PD-1 and anti-PD-L1 antibodies block PD-1/PD-L1 interactions, leading to enhanced T cell cytotoxicity towards cancer cells and increased sensitivity to interferon-induced apoptosis in cancer cells. (b) Plasma soluble FKN is a biomarker for immune cell diversity in peripheral blood from human NSCLC patients. Left: SPADE 3 hierarchical clustering of immune cell types in peripheral blood identified via high-dimensional flow cytometry in long-term responder patients to PD-1/PD-L1 blockade. Right: same as left but in non-responder patients [67]. The number of branches indicate the phenotypic diversity of immune cell types. Major lineages are grouped and indicated in the cluster trees. Mo, monocytes; NC-Mo, non-classical monocytes; G-MDSCs, granulocytic myeloid-derived suppressor cells; Neu, neutrophils. NK, natural killer cells. (c) FKN anti-tumor activities are dependent on NK and T cells. The graph shows a Kaplan–Meier survival plot in mice transplanted with lung cancer cells expressing soluble FKN, in which CD4, CD8, or NK cells have been depleted. FKN-dependent anti-tumor activities are eliminated following NK and T cell depletion [67]. **, indicates very significant differences by the Log-Rank test (p < 0.01).
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