Tumor-derived semaphorin 4A improves PD-1–blocking antibody efficacy by enhancing CD8 <sup>+</sup> T cell cytotoxicity and proliferation
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- Yujiro Naito
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Shohei Koyama
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Kentaro Masuhiro
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Takashi Hirai
- Department of Immunopathology, World Premier International Research Center (WPI), Immunology Frontier Research Center (IFReC), Osaka University, Suita, Osaka, Japan.
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- Takeshi Uenami
- Department of Thoracic Oncology, National Hospital Organization, Osaka Toneyama Medical Center, Toyonaka, Osaka, Japan.
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- Takako Inoue
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.
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- Akio Osa
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Hirotomo Machiyama
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Go Watanabe
- Division of Cancer Immunology, Research Institute/Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Kashiwa,Chiba, and Tokyo, Japan.
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- Nicolas Sax
- KOTAI Biotechnologies Inc., Suita, Osaka, Japan.
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- Jordan Villa
- KOTAI Biotechnologies Inc., Suita, Osaka, Japan.
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- Yumi Kinugasa-Katayama
- Department of Cellular Immunology, Research Institute for Microbial Diseases (RIMD), Osaka University, Suita, Osaka, Japan.
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- Satoshi Nojima
- Department of Pathology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Moto Yaga
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Yuki Hosono
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Daisuke Okuzaki
- Single Cell Genomics, Human Immunology, WPI, IFReC, Osaka University, Suita, Osaka, Japan.
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- Shingo Satoh
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Takeshi Tsuda
- Department of Otorhinolaryngology–Head and Neck Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Yoshimitsu Nakanishi
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Yasuhiko Suga
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Takayoshi Morita
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Kiyoharu Fukushima
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Masayuki Nishide
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Takayuki Shiroyama
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Kotaro Miyake
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Kota Iwahori
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Haruhiko Hirata
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Izumi Nagatomo
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Yukihiro Yano
- Department of Thoracic Oncology, National Hospital Organization, Osaka Toneyama Medical Center, Toyonaka, Osaka, Japan.
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- Motohiro Tamiya
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.
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- Toru Kumagai
- Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan.
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- Norihiko Takemoto
- Department of Otorhinolaryngology–Head and Neck Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Hidenori Inohara
- Department of Otorhinolaryngology–Head and Neck Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Sho Yamasaki
- Laboratory of Molecular Immunology, WPI, IFReC, Osaka University, Suita, Osaka, Japan.
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- Kazuo Yamashita
- KOTAI Biotechnologies Inc., Suita, Osaka, Japan.
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- Taiki Aoshi
- Department of Cellular Immunology, Research Institute for Microbial Diseases (RIMD), Osaka University, Suita, Osaka, Japan.
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- Esra A. Akbay
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
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- Naoki Hosen
- Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives (OTRI), Osaka University, Suita, Osaka, Japan.
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- Yasushi Shintani
- Department of General Thoracic Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Hyota Takamatsu
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Masahide Mori
- Department of Thoracic Oncology, National Hospital Organization, Osaka Toneyama Medical Center, Toyonaka, Osaka, Japan.
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- Yoshito Takeda
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
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- Atsushi Kumanogoh
- Department of Respiratory Medicine and Clinical Immunology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
抄録
<jats:p> Immune checkpoint inhibitors (ICIs) have caused revolutionary changes in cancer treatment, but low response rates remain a challenge. Semaphorin 4A (Sema4A) modulates the immune system through multiple mechanisms in mice, although the role of human Sema4A in the tumor microenvironment remains unclear. This study demonstrates that histologically Sema4A-positive non–small cell lung cancer (NSCLC) responded significantly better to anti–programmed cell death 1 (PD-1) antibody than Sema4A-negative NSCLC. Intriguingly, SEMA4A expression in human NSCLC was mainly derived from tumor cells and was associated with T cell activation. Sema4A promoted cytotoxicity and proliferation of tumor-specific CD8 <jats:sup>+</jats:sup> T cells without terminal exhaustion by enhancing mammalian target of rapamycin complex 1 and polyamine synthesis, which led to improved efficacy of PD-1 inhibitors in murine models. Improved T cell activation by recombinant Sema4A was also confirmed using isolated tumor-infiltrating T cells from patients with cancer. Thus, Sema4A might be a promising therapeutic target and biomarker for predicting and promoting ICI efficacy. </jats:p>
収録刊行物
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- Science Advances
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Science Advances 9 (20), 2023-05-19
American Association for the Advancement of Science (AAAS)