The CCL2-CCR4 Axis Promotes Regulatory T Cell Trafficking to Canine Glioma Tissues

Area of Science:

• Comparative oncology
• Immunology
• Neuro-oncology

Background:

• Canine glioma serves as a valuable translational model for human glioblastoma.
• Both conditions exhibit molecular similarities, including the accumulation of immunosuppressive regulatory T cells (Tregs).
• Understanding Treg recruitment mechanisms in dogs can inform human glioblastoma treatment strategies.

Purpose of the Study:

• To investigate the C-C motif chemokine 2 (CCL2) and chemokine receptor 4 (CCR4) signaling axis in canine glioma.
• To determine the role of this axis in regulatory T cell (Treg) recruitment and immunosuppression in canine glioma.
• To establish a rationale for targeting this pathway in translational clinical studies for human glioblastoma.

Main Methods:

• In vitro experiments using canine Tregs and patient-derived canine glioma cell lines.
• Development of a flow cytometry gating strategy to identify and isolate FOXP3+ Tregs.
• Assessment of canine Treg migration in response to CCL2 and glioma cell line supernatants, and the effect of CCL2-CCR4 axis blockade.

Main Results:

• Canine CD4+CD25high T cells were confirmed as Tregs based on FOXP3 and CCR4 expression.
• CCL2 significantly enhanced canine Treg migration, as did glioma cell line supernatants.
• Blockade of the CCL2-CCR4 axis markedly reduced canine Treg migration, and CCL2 expression was upregulated in glioma cells upon Treg co-culture.

Conclusions:

• The CCL2-CCR4 axis is validated as a bi-directional signaling pathway in canine high-grade glioma.
• This axis promotes immunosuppression and tumor growth by mediating Treg-glioma interactions.
• Findings support the CCL2-CCR4 axis as a potential therapeutic target for canine and human glioblastoma.