Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclusters
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...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-06-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38512-7 |
| _version_ | 1797806640579215360 |
|---|---|
| author | 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 Tadashi Yokosuka |
| author_facet | 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 Tadashi Yokosuka |
| author_sort | Wataru Nishi |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-13T06:10:21Z |
| format | Article |
| id | doaj.art-504d7a530e5c44459a41bf162dcb82a0 |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-13T06:10:21Z |
| publishDate | 2023-06-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-504d7a530e5c44459a41bf162dcb82a02023-06-11T11:19:05ZengNature PortfolioNature Communications2041-17232023-06-0114111610.1038/s41467-023-38512-7Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclustersWataru Nishi0Ei Wakamatsu1Hiroaki Machiyama2Ryohei Matsushima3Kensho Saito4Yosuke Yoshida5Tetsushi Nishikawa6Tomohiro Takehara7Hiroko Toyota8Masae Furuhata9Hitoshi Nishijima10Arata Takeuchi11Miyuki Azuma12Makoto Suzuki13Tadashi Yokosuka14Department of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto UniversityDepartment of Immunology, Tokyo Medical UniversityDepartment of Immunology, Tokyo Medical UniversityDepartment of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto UniversityDepartment of Immunology, Tokyo Medical UniversityDepartment of Immunology, Tokyo Medical UniversityDepartment of Immunology, Tokyo Medical UniversityDivision of Pulmonary Medicine, Department of Medicine, Keio University School of MedicineDepartment of Immunology, Tokyo Medical UniversityDepartment of Immunology, Tokyo Medical UniversityDepartment of Immunology, Tokyo Medical UniversityDepartment of Immunology, Tokyo Medical UniversityDepartment of Molecular Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental UniversityDepartment of Thoracic Surgery, Graduate School of Medical Sciences, Kumamoto UniversityDepartment of Immunology, Tokyo Medical UniversityAbstract 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.https://doi.org/10.1038/s41467-023-38512-7 |
| spellingShingle | 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 Tadashi Yokosuka Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclusters Nature Communications |
| title | Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclusters |
| title_full | Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclusters |
| title_fullStr | Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclusters |
| title_full_unstemmed | Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclusters |
| title_short | Evaluation of therapeutic PD-1 antibodies by an advanced single-molecule imaging system detecting human PD-1 microclusters |
| title_sort | evaluation of therapeutic pd 1 antibodies by an advanced single molecule imaging system detecting human pd 1 microclusters |
| url | https://doi.org/10.1038/s41467-023-38512-7 |
| work_keys_str_mv | AT watarunishi evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT eiwakamatsu evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT hiroakimachiyama evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT ryoheimatsushima evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT kenshosaito evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT yosukeyoshida evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT tetsushinishikawa evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT tomohirotakehara evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT hirokotoyota evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT masaefuruhata evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT hitoshinishijima evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT aratatakeuchi evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT miyukiazuma evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT makotosuzuki evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters AT tadashiyokosuka evaluationoftherapeuticpd1antibodiesbyanadvancedsinglemoleculeimagingsystemdetectinghumanpd1microclusters |