Immunological synapse formation as a key mechanism in T cell-dependent bispecific antibody-mediated immune activation and cytotoxicity
Abstract T cell-dependent bispecific antibodies (TDBs) are next-generation antibody therapies that link cancer cells and T cells to achieve potent antitumor effects. Despite the successful development of TDBs for hematological malignancies, their efficacy against solid tumors remains limited. Overco...
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| Format: | Article |
| Language: | English |
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Springer
2025-06-01
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| Series: | Cancer Immunology, Immunotherapy |
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| Online Access: | https://doi.org/10.1007/s00262-025-04036-w |
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| author | Rikuto Nakamura Ryo Tsumura Takahiro Anzai Ryutaro Asano Masahiro Yasunaga |
| author_facet | Rikuto Nakamura Ryo Tsumura Takahiro Anzai Ryutaro Asano Masahiro Yasunaga |
| author_sort | Rikuto Nakamura |
| collection | DOAJ |
| description | Abstract T cell-dependent bispecific antibodies (TDBs) are next-generation antibody therapies that link cancer cells and T cells to achieve potent antitumor effects. Despite the successful development of TDBs for hematological malignancies, their efficacy against solid tumors remains limited. Overcoming this challenge requires a deeper understanding of their mechanisms of action. While the basic process of immunological synapse (IS) formation and T cell activation by TDB is known, the detailed effects of IS on the bystander effect and T cell migration, both crucial for therapeutic efficacy, remain unclear. This study investigated these mechanisms using an EGFR/CD3 TDB (hEx3) and EGFR knockout cancer cells (KO). The results revealed that IS formation by TDB induced a bystander effect, leading to damage in surrounding KO, with the extent depending on the proportion of EGFR-positive wild-type cancer cells (WT) and the duration of co-culture. Furthermore, IS formation significantly enhanced T cell cytokine and chemokine secretion, promoting T cell migration. These findings provide critical insights into TDB efficacy mechanisms and highlight the importance of evaluating IS formation in developing new antibody drugs. Establishing a reliable system for assessing IS formation will be essential for advancing TDBs and other antibody-based therapies, particularly against solid tumors. |
| format | Article |
| id | doaj-art-5d9bc4e6842a47ccae3dd87d39457d46 |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-5d9bc4e6842a47ccae3dd87d39457d462025-08-20T04:02:57ZengSpringerCancer Immunology, Immunotherapy1432-08512025-06-0174811110.1007/s00262-025-04036-wImmunological synapse formation as a key mechanism in T cell-dependent bispecific antibody-mediated immune activation and cytotoxicityRikuto Nakamura0Ryo Tsumura1Takahiro Anzai2Ryutaro Asano3Masahiro Yasunaga4Division of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer CenterDivision of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer CenterDivision of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer CenterDepartment of Biotechnology and Life Science, Graduate School of Engineering, Tokyo University of Agriculture and TechnologyDivision of Developmental Therapeutics, Exploratory Oncology Research and Clinical Trial Center, National Cancer CenterAbstract T cell-dependent bispecific antibodies (TDBs) are next-generation antibody therapies that link cancer cells and T cells to achieve potent antitumor effects. Despite the successful development of TDBs for hematological malignancies, their efficacy against solid tumors remains limited. Overcoming this challenge requires a deeper understanding of their mechanisms of action. While the basic process of immunological synapse (IS) formation and T cell activation by TDB is known, the detailed effects of IS on the bystander effect and T cell migration, both crucial for therapeutic efficacy, remain unclear. This study investigated these mechanisms using an EGFR/CD3 TDB (hEx3) and EGFR knockout cancer cells (KO). The results revealed that IS formation by TDB induced a bystander effect, leading to damage in surrounding KO, with the extent depending on the proportion of EGFR-positive wild-type cancer cells (WT) and the duration of co-culture. Furthermore, IS formation significantly enhanced T cell cytokine and chemokine secretion, promoting T cell migration. These findings provide critical insights into TDB efficacy mechanisms and highlight the importance of evaluating IS formation in developing new antibody drugs. Establishing a reliable system for assessing IS formation will be essential for advancing TDBs and other antibody-based therapies, particularly against solid tumors.https://doi.org/10.1007/s00262-025-04036-wAntibody therapeuticsBispecific antibody (BsAb)T cell-dependent bispecific antibody (TDB)Immunological synapse (IS)ImmunotherapyPancreatic cancer |
| spellingShingle | Rikuto Nakamura Ryo Tsumura Takahiro Anzai Ryutaro Asano Masahiro Yasunaga Immunological synapse formation as a key mechanism in T cell-dependent bispecific antibody-mediated immune activation and cytotoxicity Cancer Immunology, Immunotherapy Antibody therapeutics Bispecific antibody (BsAb) T cell-dependent bispecific antibody (TDB) Immunological synapse (IS) Immunotherapy Pancreatic cancer |
| title | Immunological synapse formation as a key mechanism in T cell-dependent bispecific antibody-mediated immune activation and cytotoxicity |
| title_full | Immunological synapse formation as a key mechanism in T cell-dependent bispecific antibody-mediated immune activation and cytotoxicity |
| title_fullStr | Immunological synapse formation as a key mechanism in T cell-dependent bispecific antibody-mediated immune activation and cytotoxicity |
| title_full_unstemmed | Immunological synapse formation as a key mechanism in T cell-dependent bispecific antibody-mediated immune activation and cytotoxicity |
| title_short | Immunological synapse formation as a key mechanism in T cell-dependent bispecific antibody-mediated immune activation and cytotoxicity |
| title_sort | immunological synapse formation as a key mechanism in t cell dependent bispecific antibody mediated immune activation and cytotoxicity |
| topic | Antibody therapeutics Bispecific antibody (BsAb) T cell-dependent bispecific antibody (TDB) Immunological synapse (IS) Immunotherapy Pancreatic cancer |
| url | https://doi.org/10.1007/s00262-025-04036-w |
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