Depletion of central memory CD8+ T cells might impede the antitumor therapeutic effect of Mogamulizumab

Yuka Maeda, Hisashi Wada (), Daisuke Sugiyama, Takuro Saito, Takuma Irie, Kota Itahashi, Kodai Minoura, Susumu Suzuki, Takashi Kojima, Kazuhiro Kakimi, Jun Nakajima, Takeru Funakoshi, Shinsuke Iida, Mikio Oka, Teppei Shimamura, Toshihiko Doi, Yuichiro Doki, Eiichi Nakayama, Ryuzo Ueda () and Hiroyoshi Nishikawa ()
Additional contact information
Yuka Maeda: Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center
Hisashi Wada: Osaka University Graduate School of Medicine
Daisuke Sugiyama: Nagoya University Graduate School of Medicine
Takuro Saito: Osaka University Graduate School of Medicine
Takuma Irie: Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center
Kota Itahashi: Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center
Kodai Minoura: Nagoya University Graduate School of Medicine
Susumu Suzuki: Aichi Medical University
Takashi Kojima: National Cancer Center Hospital East
Kazuhiro Kakimi: The University of Tokyo Hospital
Jun Nakajima: Graduate School of Medicine, The University of Tokyo
Takeru Funakoshi: Keio University School of Medicine
Shinsuke Iida: Nagoya City University Institute of Medical and Pharmaceutical Sciences
Mikio Oka: Kawasaki Medical School
Teppei Shimamura: Nagoya University Graduate School of Medicine
Toshihiko Doi: National Cancer Center Hospital East
Yuichiro Doki: Osaka University Graduate School of Medicine
Eiichi Nakayama: Kawasaki University of Medical Welfare
Ryuzo Ueda: Aichi Medical University
Hiroyoshi Nishikawa: Research Institute/Exploratory Oncology Research & Clinical Trial Center (EPOC), National Cancer Center

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-27574-0

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