Abstract
Regulatory T (Treg) cells are important negative regulators of immune homeostasis, but in cancers they tone down the anti-tumor immune response. They are distinguished by high expression levels of the chemokine receptor CCR4, hence their targeting by the anti-CCR4 monoclonal antibody mogamulizumab holds therapeutic promise. Here we show that despite a significant reduction in peripheral effector Treg cells, clinical responses are minimal in a cohort of patients with advanced CCR4-negative solid cancer in a phase Ib study (NCT01929486). Comprehensive immune-monitoring reveals that the abundance of CCR4-expressing central memory CD8+ T cells that are known to play roles in the antitumor immune response is reduced. In long survivors, characterised by lower CCR4 expression in their central memory CD8+ T cells possessed and/or NK cells with an exhausted phenotype, cell numbers are eventually maintained. Our study thus shows that mogamulizumab doses that are currently administered to patients in clinical studies may not differentiate between targeting effector Treg cells and central memory CD8+ T cells, and dosage refinement might be necessary to avoid depletion of effector components during immune therapy.
Highlights
Regulatory T (Treg) cells are important negative regulators of immune homeostasis, but in cancers they tone down the anti-tumor immune response
We found an unexpected reduction of central memory CD8+ T cells, which reportedly play an important role in antitumor activity in cancer immunotherapy[24,25], harboring CCR4 expression accompanied by Treg cell reduction after mogamulizumab administration; this indicates the importance of developing more specific Treg cell-targeted therapies
Given the uncoupling of clinical efficacy and CCR4 expression in effector Treg (eTreg) cells and central memory CD8+ T cells, we further explored the potential involvement of NK cell function in the clinical efficacy of mogamulizumab treatment because mogamulizumab possesses enhanced antibody-dependent cellular cytotoxicity (ADCC) activity via a defucosylated Fc region[28]
Summary
Regulatory T (Treg) cells are important negative regulators of immune homeostasis, but in cancers they tone down the anti-tumor immune response They are distinguished by high expression levels of the chemokine receptor CCR4, their targeting by the anti-CCR4 monoclonal antibody mogamulizumab holds therapeutic promise. A phase 1a clinical trial of Treg cell depletion by the administration of anti-CCR4 mAb (mogamulizumab, KW-0761) for advanced or recurrent solid tumor patients revealed a significant reduction of eTreg cells in the peripheral blood[22]. We found an unexpected reduction of central memory CD8+ T cells, which reportedly play an important role in antitumor activity in cancer immunotherapy[24,25], harboring CCR4 expression accompanied by Treg cell reduction after mogamulizumab administration; this indicates the importance of developing more specific Treg cell-targeted therapies
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