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Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclusters

Author

Listed:
  • Wataru Nishi

    (Kumamoto University
    Tokyo Medical University)

  • Ei Wakamatsu

    (Tokyo Medical University)

  • Hiroaki Machiyama

    (Tokyo Medical University)

  • Ryohei Matsushima

    (Kumamoto University
    Tokyo Medical University)

  • Kensho Saito

    (Tokyo Medical University
    Tokyo University of Pharmacy and Life Sciences)

  • Yosuke Yoshida

    (Tokyo Medical University
    Tokyo Medical University)

  • Tetsushi Nishikawa

    (Tokyo Medical University
    Tokyo Medical University)

  • Tomohiro Takehara

    (Keio University School of Medicine)

  • Hiroko Toyota

    (Tokyo Medical University)

  • Masae Furuhata

    (Tokyo Medical University)

  • Hitoshi Nishijima

    (Tokyo Medical University)

  • Arata Takeuchi

    (Tokyo Medical University)

  • Miyuki Azuma

    (Tokyo Medical and Dental University)

  • Makoto Suzuki

    (Kumamoto University)

  • Tadashi Yokosuka

    (Tokyo Medical University)

Abstract

With recent advances in immune checkpoint inhibitors (ICIs), immunotherapy has become the standard treatment for various malignant tumors. Their indications and dosages have been determined empirically, taking individually conducted clinical trials into consideration, but without a standard method to evaluate them. Here we establish an advanced imaging system to visualize human PD-1 microclusters, in which a minimal T cell receptor (TCR) signaling unit co-localizes with the inhibitory co-receptor PD-1 in vitro. In these microclusters PD-1 dephosphorylates both the TCR/CD3 complex and its downstream signaling molecules via the recruitment of a phosphatase, SHP2, upon stimulation with the ligand hPD-L1. In this system, blocking antibodies for hPD-1-hPD-L1 binding inhibits hPD-1 microcluster formation, and each therapeutic antibody (pembrolizumab, nivolumab, durvalumab and atezolizumab) is characterized by a proprietary optimal concentration and combinatorial efficiency enhancement. We propose that our imaging system could digitally evaluate PD-1-mediated T cell suppression to evaluate their clinical usefulness and to develop the most suitable combinations among ICIs or between ICIs and conventional cancer treatments.

Suggested Citation

  • Wataru Nishi & Ei Wakamatsu & Hiroaki Machiyama & Ryohei Matsushima & Kensho Saito & Yosuke Yoshida & Tetsushi Nishikawa & Tomohiro Takehara & Hiroko Toyota & Masae Furuhata & Hitoshi Nishijima & Arat, 2023. "Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclusters," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38512-7
    DOI: 10.1038/s41467-023-38512-7
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    References listed on IDEAS

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    1. Ju Yeon Lee & Hyun Tae Lee & Woori Shin & Jongseok Chae & Jaemo Choi & Sung Hyun Kim & Heejin Lim & Tae Won Heo & Kyeong Young Park & Yeon Ji Lee & Seong Eon Ryu & Ji Young Son & Jee Un Lee & Yong-Seo, 2016. "Structural basis of checkpoint blockade by monoclonal antibodies in cancer immunotherapy," Nature Communications, Nature, vol. 7(1), pages 1-10, December.
    2. Colin R. F. Monks & Benjamin A. Freiberg & Hannah Kupfer & Noah Sciaky & Abraham Kupfer, 1998. "Three-dimensional segregation of supramolecular activation clusters in T cells," Nature, Nature, vol. 395(6697), pages 82-86, September.
    3. Xiangguo Qiu & Gary Wong & Jonathan Audet & Alexander Bello & Lisa Fernando & Judie B. Alimonti & Hugues Fausther-Bovendo & Haiyan Wei & Jenna Aviles & Ernie Hiatt & Ashley Johnson & Josh Morton & Kel, 2014. "Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp," Nature, Nature, vol. 514(7520), pages 47-53, October.
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