The CCL2-CCR4 axis promotes Regulatory T cell trafficking to canine glioma tissues.

Autor: Panek WK; Department of Surgical and Radiological Sciences, University of California, Davis, One Shields Avenue, 2112 Tupper Hall, Davis, CA, 95616-5270, USA. wkp@upenn.edu.; Department of Clinical Sciences & Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, 380 South University Avenue, 419 Hill Pavilion, Philadelphia, PA, 19104, USA. wkp@upenn.edu., Toedebusch RG; Department of Surgical and Radiological Sciences, University of California, Davis, One Shields Avenue, 2112 Tupper Hall, Davis, CA, 95616-5270, USA., Mclaughlin BE; University of California Davis, Flow Cytometry Shared Resource, Davis, CA, USA., Dickinson PJ; Department of Surgical and Radiological Sciences, University of California, Davis, One Shields Avenue, 2112 Tupper Hall, Davis, CA, 95616-5270, USA., Van Dyke JE; University of California Davis, Flow Cytometry Shared Resource, Davis, CA, USA., Woolard KD; Department of Pathology, Microbiology and Immunology, University of California, Davis, Davis, CA, USA., Berens ME; Cancer and Cell Biology Division, The Translational Genomics Research Institute, Phoenix, AZ, USA., Lesniak MS; Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Sturges BK; Department of Surgical and Radiological Sciences, University of California, Davis, One Shields Avenue, 2112 Tupper Hall, Davis, CA, 95616-5270, USA., Vernau KM; Department of Surgical and Radiological Sciences, University of California, Davis, One Shields Avenue, 2112 Tupper Hall, Davis, CA, 95616-5270, USA., Li C; Department of Surgical and Radiological Sciences, University of California, Davis, One Shields Avenue, 2112 Tupper Hall, Davis, CA, 95616-5270, USA., Miska J; Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA., Toedebusch CM; Department of Surgical and Radiological Sciences, University of California, Davis, One Shields Avenue, 2112 Tupper Hall, Davis, CA, 95616-5270, USA. cmtoedebusch@ucdavis.edu.
Jazyk: angličtina
Zdroj: Journal of neuro-oncology [J Neurooncol] 2024 Sep; Vol. 169 (3), pp. 647-658. Date of Electronic Publication: 2024 Jul 24.
DOI: 10.1007/s11060-024-04766-4
Abstrakt: Purpose: Spontaneously occurring glioma in pet dogs is increasingly recognized as a valuable translational model for human glioblastoma. Canine high-grade glioma and human glioblastomas share many molecular similarities, including the accumulation of immunosuppressive regulatory T cells (Tregs) that inhibit anti-tumor immune responses. Identifying in dog mechanisms responsible for Treg recruitment may afford to target the cellular population driving immunosuppression, the results providing a rationale for translational clinical studies in human patients. Our group has previously identified C-C motif chemokine 2 (CCL2) as a glioma-derived T-reg chemoattractant acting on chemokine receptor 4 (CCR4) in a murine orthotopic glioma model. Recently, we demonstrated a robust increase of CCL2 in the brain tissue of canine patients bearing high-grade glioma.
Methods: We performed a series of in vitro experiments using canine Tregs and patient-derived canine glioma cell lines (GSC 1110, GSC 0514, J3T-Bg, G06A) to interrogate the CCL2-CCR4 signaling axis in the canine.
Results: We established a flow cytometry gating strategy for identifying and isolating FOXP3 + Tregs in dogs. The canine CD4 + CD25 high T-cell population was highly enriched in FOXP3 and CCR4 expression, indicating they are bona fide Tregs. Canine Treg migration was enhanced by CCL2 or by glioma cell line-derived supernatant. Blockade of the CCL2-CCR4 axis significantly reduced migration of canine Tregs. CCL2 mRNA was expressed in all glioma cell lines, and expression increased when exposed to Tregs but not CD4 + helper T-cells.
Conclusion: Our study validates CCL2-CCR4 as a bi-directional Treg-glioma immunosuppressive and tumor-promoting axis in canine high-grade glioma.
(© 2024. The Author(s).)
Databáze: MEDLINE
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