Trogocytosis and fratricide killing impede MSLN-directed CAR T cell functionality
Successful translation of chimeric antigen receptor (CAR) T cell therapy for the treatment of solid tumors has proved to be troublesome, mainly due to the complex tumor microenvironment promoting T cell dysfunction and antigen heterogeneity. Mesothelin (MSLN) has emerged as an attractive target for...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-12-01
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| Series: | OncoImmunology |
| Subjects: | |
| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2093426 |
| _version_ | 1818249480617590784 |
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| author | Esther Schoutrop Stefanie Renken Isabella Micallef Nilsson Paula Hahn Thomas Poiret Rolf Kiessling Stina L Wickström Jonas Mattsson Isabelle Magalhaes |
| author_facet | Esther Schoutrop Stefanie Renken Isabella Micallef Nilsson Paula Hahn Thomas Poiret Rolf Kiessling Stina L Wickström Jonas Mattsson Isabelle Magalhaes |
| author_sort | Esther Schoutrop |
| collection | DOAJ |
| description | Successful translation of chimeric antigen receptor (CAR) T cell therapy for the treatment of solid tumors has proved to be troublesome, mainly due to the complex tumor microenvironment promoting T cell dysfunction and antigen heterogeneity. Mesothelin (MSLN) has emerged as an attractive target for CAR T cell therapy of several solid malignancies, including ovarian cancer. To improve clinical response rates with MSLN-CAR T cells, a better understanding of the mechanisms impacting CAR T cell functionality in vitro is crucial. Here, we demonstrated superior cytolytic capacity of CD28-costimulated MSLN-CAR T cells (M28z) relative to 4–1BB-costimulated MSLN-CAR T cells (MBBz). Furthermore, CD28-costimulated MSLN CAR T cells displayed enhanced cytolytic capacity against tumor spheroids with heterogeneous MSLN expression compared to MBBz CAR T cells. In this study, we identified CAR-mediated trogocytosis as a potential impeding factor for successful MSLN-CAR T cell therapy due to fratricide killing and contributing to tumor antigen heterogeneity. Moreover, we link antigen-dependent upregulation of LAG-3 with reduced CAR T cell functionality. Taken together, our study highlights the therapeutic potential and bottlenecks of MSLN-CAR T cells, providing a rationale for combinatorial treatment strategies. |
| first_indexed | 2024-12-12T15:37:10Z |
| format | Article |
| id | doaj.art-33f5ba011cf646ee88cac171d4e0b61d |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-12T15:37:10Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-33f5ba011cf646ee88cac171d4e0b61d2022-12-22T00:19:59ZengTaylor & Francis GroupOncoImmunology2162-402X2022-12-0111110.1080/2162402X.2022.2093426Trogocytosis and fratricide killing impede MSLN-directed CAR T cell functionalityEsther Schoutrop0Stefanie Renken1Isabella Micallef Nilsson2Paula Hahn3Thomas Poiret4Rolf Kiessling5Stina L Wickström6Jonas Mattsson7Isabelle Magalhaes8Department of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenDepartment of Oncology-Pathology, Karolinska Institutet, Stockholm, SwedenSuccessful translation of chimeric antigen receptor (CAR) T cell therapy for the treatment of solid tumors has proved to be troublesome, mainly due to the complex tumor microenvironment promoting T cell dysfunction and antigen heterogeneity. Mesothelin (MSLN) has emerged as an attractive target for CAR T cell therapy of several solid malignancies, including ovarian cancer. To improve clinical response rates with MSLN-CAR T cells, a better understanding of the mechanisms impacting CAR T cell functionality in vitro is crucial. Here, we demonstrated superior cytolytic capacity of CD28-costimulated MSLN-CAR T cells (M28z) relative to 4–1BB-costimulated MSLN-CAR T cells (MBBz). Furthermore, CD28-costimulated MSLN CAR T cells displayed enhanced cytolytic capacity against tumor spheroids with heterogeneous MSLN expression compared to MBBz CAR T cells. In this study, we identified CAR-mediated trogocytosis as a potential impeding factor for successful MSLN-CAR T cell therapy due to fratricide killing and contributing to tumor antigen heterogeneity. Moreover, we link antigen-dependent upregulation of LAG-3 with reduced CAR T cell functionality. Taken together, our study highlights the therapeutic potential and bottlenecks of MSLN-CAR T cells, providing a rationale for combinatorial treatment strategies.https://www.tandfonline.com/doi/10.1080/2162402X.2022.2093426CAR T cellsmesothelintrogocytosisovarian cancerimmune escapefratricide killing |
| spellingShingle | Esther Schoutrop Stefanie Renken Isabella Micallef Nilsson Paula Hahn Thomas Poiret Rolf Kiessling Stina L Wickström Jonas Mattsson Isabelle Magalhaes Trogocytosis and fratricide killing impede MSLN-directed CAR T cell functionality OncoImmunology CAR T cells mesothelin trogocytosis ovarian cancer immune escape fratricide killing |
| title | Trogocytosis and fratricide killing impede MSLN-directed CAR T cell functionality |
| title_full | Trogocytosis and fratricide killing impede MSLN-directed CAR T cell functionality |
| title_fullStr | Trogocytosis and fratricide killing impede MSLN-directed CAR T cell functionality |
| title_full_unstemmed | Trogocytosis and fratricide killing impede MSLN-directed CAR T cell functionality |
| title_short | Trogocytosis and fratricide killing impede MSLN-directed CAR T cell functionality |
| title_sort | trogocytosis and fratricide killing impede msln directed car t cell functionality |
| topic | CAR T cells mesothelin trogocytosis ovarian cancer immune escape fratricide killing |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2093426 |
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