Small-Molecule CCR4 Antagonists in Cutaneous T-cell Lymphoma.

Authors

José S Enriquez
Xiaohong Wang
Loka Reddy Velatooru
Wei Han
Pedram Bijani
Xiao Ni

Publication Date

10-1-2024

Journal

Cancer Research Communications

Abstract

Mycosis fungoides (MF) and Sézary syndrome (SS) are two most common types of cutaneous T-cell lymphoma (CTCL). Despite advances in understanding the pathogenesis of MF and SS, effective treatments remain limited. CC chemokine receptor-4 (CCR4) is highly expressed on CTCL cells and serves as a great therapeutic target. Mogamulizumab, an FDA-approved anti-CCR4 antibody, has shown efficacy in treating MF/SS; however, its side effects have raised concerns, underscoring the need for more effective and less toxic CCR4-targeted therapies. Although small-molecule CCR4 antagonists have been studied in other diseases involving CCR4⁺ Th2 cells and regulatory T cells, their effects in CTCL have not been previously explored. This study assessed the effects of two small-molecule CCR4 antagonists: C021 (class-I) and AZD-2098 (class-II) in MF-derived cell line (MJ) and SS-derived cell line (HuT 78) in vitro and in vivo. As per results, both C021 and AZD-2098 inhibited chemotactic responses to CCL17 and CCL22 in MJ and HuT 78 cells. However, only C021 downregulated CCR4 expression, inhibited cell proliferation, induced cell apoptosis and cell-cycle arrest, and decreased colony formation in MJ and HuT 78 cells in vitro. Furthermore, only C021 inhibited tumor growth in CTCL xenograft mice in vivo. These findings suggest that class-I CCR4 antagonists such as C021 exert more potent antitumor effects on CTCL cells in vitro and in vivo than do class-II CCR4 antagonists like AZD-2098, highlighting their potential for clinical application.

Significance:

Our findings are of interest to readers because they bring new evidence that small-molecule CCR4 antagonists may be an alternative therapeutic strategy to target CCR4⁺ CTCL cells. They may inhibit CCR4 function but not eradicate cells, so the side effects may be avoided or minimized.

Keywords

Humans, Receptors, CCR4, Lymphoma, T-Cell, Cutaneous, Skin Neoplasms, Antineoplastic Agents

DOI

10.1158/2767-9764.CRC-24-0297

PMID

39302105

PMCID

PMC11494885

PubMedCentral® Posted Date

10-22-2024

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes