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Cancer Immunology Research
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Research Article

Transient Depletion of CD4+ Cells Induces Remodeling of the TCR Repertoire in Gastrointestinal Cancer

Hiroyasu Aoki, Satoshi Ueha, Shigeyuki Shichino, Haru Ogiwara, Kohei Shitara, Manami Shimomura, Toshihiro Suzuki, Tetsuya Nakatsura, Makiko Yamashita, Shigehisa Kitano, Sakiko Kuroda, Masashi Wakabayashi, Makoto Kurachi, Satoru Ito, Toshihiko Doi and Kouji Matsushima
Hiroyasu Aoki
1Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
2Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan.
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Satoshi Ueha
1Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
2Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan.
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  • For correspondence: ueha@rs.tus.ac.jp
Shigeyuki Shichino
1Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
2Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan.
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Haru Ogiwara
1Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
2Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan.
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Kohei Shitara
3Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
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Manami Shimomura
4Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
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Toshihiro Suzuki
4Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
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Tetsuya Nakatsura
4Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Kashiwa, Japan.
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Makiko Yamashita
5Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
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Shigehisa Kitano
5Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
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  • ORCID record for Shigehisa Kitano
Sakiko Kuroda
6Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan.
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Masashi Wakabayashi
6Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan.
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Makoto Kurachi
7Department of Molecular Genetics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.
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Satoru Ito
1Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
8IDAC Theranostics, Inc., Tokyo, Japan.
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Toshihiko Doi
9Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan.
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Kouji Matsushima
1Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
2Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science, Tokyo, Japan.
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DOI: 10.1158/2326-6066.CIR-20-0989
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Abstract

Antibody-mediated transient depletion of CD4+ cells enhances the expansion of tumor-reactive CD8+ T cells and exhibits robust antitumor effects in preclinical and clinical studies. To investigate the clonal T-cell responses following transient CD4+ cell depletion in patients with cancer, we conducted a temporal analysis of the T-cell receptor (TCR) repertoire in the first-in-human clinical trial of IT1208, a defucosylated humanized monoclonal anti-CD4. Transient depletion of CD4+ cells promoted replacement of T-cell clones among CD4+ and CD8+ T cells in the blood. This replacement of the TCR repertoire was associated with the extent of CD4+ T-cell depletion and an increase in CD8+ T-cell count in the blood. Next, we focused on T-cell clones overlapping between the blood and tumor in order to track tumor-associated T-cell clones in the blood. The total frequency of blood–tumor overlapping clones tended to increase in patients receiving a depleting dose of anti-CD4, which was accompanied by the replacement of overlapping clones. The greater expansion of CD8+ overlapping clones was commonly observed in the patients who achieved tumor shrinkage. These results suggested that the clonal replacement of the TCR repertoire induced by transient CD4+ cell depletion was accompanied by the expansion of tumor-reactive T-cell clones that mediated antitumor responses. Our findings propose beneficial remodeling of the TCR repertoire following transient CD4+ cell depletion and provide novel insight into the antitumor effects of monoclonal anti-CD4 treatment in patients with cancer.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

  • Cancer Immunol Res 2021;XX:XX–XX

  • Received December 3, 2020.
  • Revision received January 20, 2021.
  • Accepted March 3, 2021.
  • Published first March 5, 2021.
  • ©2021 American Association for Cancer Research.
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This OnlineFirst version was published on April 7, 2021
doi: 10.1158/2326-6066.CIR-20-0989

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Transient Depletion of CD4+ Cells Induces Remodeling of the TCR Repertoire in Gastrointestinal Cancer
Hiroyasu Aoki, Satoshi Ueha, Shigeyuki Shichino, Haru Ogiwara, Kohei Shitara, Manami Shimomura, Toshihiro Suzuki, Tetsuya Nakatsura, Makiko Yamashita, Shigehisa Kitano, Sakiko Kuroda, Masashi Wakabayashi, Makoto Kurachi, Satoru Ito, Toshihiko Doi and Kouji Matsushima
Cancer Immunol Res April 7 2021 DOI: 10.1158/2326-6066.CIR-20-0989

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Transient Depletion of CD4+ Cells Induces Remodeling of the TCR Repertoire in Gastrointestinal Cancer
Hiroyasu Aoki, Satoshi Ueha, Shigeyuki Shichino, Haru Ogiwara, Kohei Shitara, Manami Shimomura, Toshihiro Suzuki, Tetsuya Nakatsura, Makiko Yamashita, Shigehisa Kitano, Sakiko Kuroda, Masashi Wakabayashi, Makoto Kurachi, Satoru Ito, Toshihiko Doi and Kouji Matsushima
Cancer Immunol Res April 7 2021 DOI: 10.1158/2326-6066.CIR-20-0989
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