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Trametinib improves Treg selectivity of anti-CCR4 antibody by regulating CCR4 expression in CTLs in oral squamous cell carcinoma
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Trametinib improves Treg selectivity of anti-CCR4 antibody by regulating CCR4 expression in CTLs in oral squamous cell carcinoma
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Trametinib improves Treg selectivity of anti-CCR4 antibody by regulating CCR4 expression in CTLs in oral squamous cell carcinoma
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Journal Article
Trametinib improves Treg selectivity of anti-CCR4 antibody by regulating CCR4 expression in CTLs in oral squamous cell carcinoma
2022
Overview
Regulatory T-cells (Tregs) play a major role in suppressing anti-tumor immune responses. Mogamulizumab, an anti-CC chemokine receptor type 4 (CCR4) monoclonal antibody, depletes effector Tregs (eTregs). However, the clinical efficacy of mogamulizumab was limited in phase Ia/Ib studies for solid tumors (NCT01929486); the finding suggests that mogamulizumab may also deplete beneficial CCR4
+
CD8
+
T-cells in patients. Therefore, we focused on CTLs and aimed to identify a way to protect CCR4
+
CTLs. Here, we evaluated the association of CCR4 expression in cytotoxic T-lymphocytes (CTLs) with antigen and cytokine stimulations and kinase inhibition using cytomegalovirus antigen instead of tumor antigen. CCR4 expression in CTLs was induced by antigen stimulation (mean 3.14–29.0%), enhanced by transforming growth factor-β1 (TGF-β1) (mean 29.0–51.2%), and downregulated by trametinib with (mean 51.2–11.4%) or without TGF-β1 treatment (mean 29.0–6.98%). Phosphorylation of ERK in CD8
+
T-cells was suppressed by trametinib. Regarding the effect on immunological function of CTL, trametinib reduced cytokine production but not affected cytotoxicity. Importantly, trametinib alleviated CTL reduction by anti-CCR4 antibody without affecting eTreg depletion because CCR4 expression in eTregs was not downregulated. In conclusion, combination therapy with trametinib may improve the clinical efficacy of mogamulizumab.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 631/67
/ 692/4028
/ 692/53
/ Antigens
/ Carcinoma, Squamous Cell - metabolism
/ CD8-Positive T-Lymphocytes - metabolism
/ Extracellular signal-regulated kinase
/ Head and Neck Neoplasms - metabolism
/ Humanities and Social Sciences
/ Humans
/ Mouth Neoplasms - drug therapy
/ Mouth Neoplasms - metabolism
/ Oral squamous cell carcinoma
/ Receptors, CCR4 - metabolism
/ Science
/ Squamous Cell Carcinoma of Head and Neck - metabolism
/ T-Lymphocytes, Cytotoxic - metabolism
