CR5/CCL5 axis is linked to a poor outcome, and inhibition reduces metastasis in oral squamous cell carcinoma

• Published in: Journal of cancer research and clinical oncology Vol. 149; no. 19; pp. 17335 - 17346
• Main Authors: González-Arriagada, Wilfredo Alejandro, Coletta, Ricardo D, Lozano-Burgos, Carlo, García, Cynthia, Maripillán, Jaime, Alcayaga-Miranda, Francisca, Godínez-Pacheco, Bastián, Oyarce-Pezoa, Sebastián, Martínez-Flores, René, García, Isaac E
• Format: Journal Article
• Language: English
• Published: Germany 01-12-2023
• Subjects: Animals; Carcinoma, Squamous Cell - drug therapy; Cell Line, Tumor; Chemokine CCL5 - genetics; Chemokine CCL5 - metabolism; Head and Neck Neoplasms; Humans; Maraviroc - pharmacology; Mice; Mouth Neoplasms - drug therapy; Retrospective Studies; RNA, Small Interfering - metabolism; Squamous Cell Carcinoma of Head and Neck; Tumor Microenvironment; CCR5 receptor; Prognosis; Metastasis; Oral cancer; Survival; CCL5 chemokine
• ISSN: 1432-1335
• DOI: 10.1007/s00432-023-05443-1

The CCR5/CCL5 axis is essential for interactions between malignant cells and microenvironment components, promoting tumor progression in oral squamous cell carcinoma (OSCC). This study aims to evaluate the association of CCL5 and CCR5 with the behavior of oral cancer and assess the therapeutic potential of a CCR5 antagonist.
A retrospective study to analyze CCR5 and CCL5 expression on paraffin-embedded tissues was performed. In cell lines, rhCCL5 was added to induce CCR5-related pathways, and Maraviroc and shRNA against CCR5 were used to neutralize the receptor. Finally, an in vivo murine orthotopic xenograft model of tongue cancer was used to evaluate Maraviroc as an oncologic therapy. After 15 days, the mice were killed, and the primary tumors and cervical lymph nodes were analyzed.
The expression of CCR5 was associated with clinical stage and metastasis, and CCL5 was related to overall survival. Adding rhCCL5 induced cell proliferation, while shRNA and Maraviroc reduced it in a dose-dependent manner. Maraviroc treatment also increased apoptosis and modified cytoskeletal organization. In vivo, Maraviroc reduced neck metastasis.
The effects of CCR5 antagonists in OSCC have been poorly studied, and this study reports in vitro and in vivo evidence for the effects of Maraviroc in OSCC. Our results suggest that the CCR5/CCL5 axis plays a role in oral cancer behavior, and that its inhibition is a promising new therapy alternative.