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

Wataru Nishi, Ei Wakamatsu, Hiroaki Machiyama, Ryohei Matsushima, Kensho Saito, Yosuke Yoshida, Tetsushi Nishikawa, Tomohiro Takehara, Hiroko Toyota, Masae Furuhata, Hitoshi Nishijima, Arata Takeuchi, Miyuki Azuma, Makoto Suzuki and Tadashi Yokosuka ()
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Wataru Nishi: Kumamoto University
Ei Wakamatsu: Tokyo Medical University
Hiroaki Machiyama: Tokyo Medical University
Ryohei Matsushima: Kumamoto University
Kensho Saito: Tokyo Medical University
Yosuke Yoshida: Tokyo Medical University
Tetsushi Nishikawa: 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

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38512-7

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