γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoids
Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-11-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1281646/full |
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| author | Junxue Dong Junxue Dong David Holthaus Christian Peters Stefanie Koster Marzieh Ehsani Alvaro Quevedo-Olmos Hilmar Berger Hilmar Berger Michal Zarobkiewicz Michal Zarobkiewicz Mandy Mangler Mandy Mangler Rajendra Kumar Gurumurthy Nina Hedemann Cindrilla Chumduri Cindrilla Chumduri Cindrilla Chumduri Dieter Kabelitz Thomas F. Meyer Thomas F. Meyer |
| author_facet | Junxue Dong Junxue Dong David Holthaus Christian Peters Stefanie Koster Marzieh Ehsani Alvaro Quevedo-Olmos Hilmar Berger Hilmar Berger Michal Zarobkiewicz Michal Zarobkiewicz Mandy Mangler Mandy Mangler Rajendra Kumar Gurumurthy Nina Hedemann Cindrilla Chumduri Cindrilla Chumduri Cindrilla Chumduri Dieter Kabelitz Thomas F. Meyer Thomas F. Meyer |
| author_sort | Junxue Dong |
| collection | DOAJ |
| description | Cervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and long-term propagation capabilities offer a promising platform for developing viable strategies. In addition to αβ T cells and natural killer (NK) cells, γδ T cells represent an immune cell population with significant therapeutic potential against both hematologic and solid tumours. To evaluate the efficacy of γδ T cells in cervical cancer treatment, we generated patient-derived healthy and cancer ectocervical organoids. Furthermore, we examined transformed healthy organoids, expressing HPV16 oncogenes E6 and E7. We analysed the effector function of in vitro expanded γδ T cells upon co-culture with organoids. Our findings demonstrated that healthy cervical organoids were less susceptible to γδ T cell-mediated cytotoxicity compared to HPV-transformed organoids and cancerous organoids. To identify the underlying pathways involved in this observed cytotoxicity, we performed bulk-RNA sequencing on the organoid lines, revealing differences in DNA-damage and cell cycle checkpoint pathways, as well as transcription of potential γδ T cell ligands. We validated these results using immunoblotting and flow cytometry. We also demonstrated the involvement of BTN3A1 and BTN2A1, crucial molecules for γδ T cell activation, as well as differential expression of PDL1/CD274 in cancer, E6/E7+ and healthy organoids. Interestingly, we observed a significant reduction in cytotoxicity upon blocking MSH2, a protein involved in DNA mismatch-repair. In summary, we established a co-culture system of γδ T cells with cervical cancer organoids, providing a novel in vitro model to optimize innovative patient-specific immunotherapies for cervical cancer. |
| first_indexed | 2024-03-09T14:45:10Z |
| format | Article |
| id | doaj.art-22cb8b5291094598b7ec152c0b00f6f2 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-03-09T14:45:10Z |
| publishDate | 2023-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-22cb8b5291094598b7ec152c0b00f6f22023-11-27T06:47:34ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-11-011410.3389/fimmu.2023.12816461281646γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoidsJunxue Dong0Junxue Dong1David Holthaus2Christian Peters3Stefanie Koster4Marzieh Ehsani5Alvaro Quevedo-Olmos6Hilmar Berger7Hilmar Berger8Michal Zarobkiewicz9Michal Zarobkiewicz10Mandy Mangler11Mandy Mangler12Rajendra Kumar Gurumurthy13Nina Hedemann14Cindrilla Chumduri15Cindrilla Chumduri16Cindrilla Chumduri17Dieter Kabelitz18Thomas F. Meyer19Thomas F. Meyer20Laboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, GermanyDepartment of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, GermanyLaboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, GermanyInstitute of Immunology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, GermanyDepartment of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, GermanyLaboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, GermanyLaboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, GermanyLaboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, GermanyDepartment of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, GermanyInstitute of Immunology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, GermanyDepartment of Clinical Immunology, Medical University of Lublin, Lublin, PolandDepartment of Gynaecology and Obstetrics, Vivantes Auguste Viktoria-Klinikum, Berlin, GermanyDepartment of Gynaecology, Charité University Medicine, Berlin, GermanyDepartment of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, GermanyDepartment of Gynaecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, GermanyDepartment of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, GermanyLaboratory of Infections, Carcinogenesis and Regeneration, Medical Biotechnology Section, Department of Biological and Chemical Engineering, Aarhus University, Aarhus, DenmarkChair of Microbiology, University of Würzburg, Würzburg, GermanyInstitute of Immunology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, GermanyLaboratory of Infection Oncology, Institute of Clinical Molecular Biology, Christian-Albrechts-Universität zu Kiel and University Hospital Schleswig-Holstein, Kiel, GermanyDepartment of Molecular Biology, Max Planck Institute for Infection Biology, Berlin, GermanyCervical cancer is a leading cause of death among women globally, primarily driven by high-risk papillomaviruses. However, the effectiveness of chemotherapy is limited, underscoring the potential of personalized immunotherapies. Patient-derived organoids, which possess cellular heterogeneity, proper epithelial architecture and functionality, and long-term propagation capabilities offer a promising platform for developing viable strategies. In addition to αβ T cells and natural killer (NK) cells, γδ T cells represent an immune cell population with significant therapeutic potential against both hematologic and solid tumours. To evaluate the efficacy of γδ T cells in cervical cancer treatment, we generated patient-derived healthy and cancer ectocervical organoids. Furthermore, we examined transformed healthy organoids, expressing HPV16 oncogenes E6 and E7. We analysed the effector function of in vitro expanded γδ T cells upon co-culture with organoids. Our findings demonstrated that healthy cervical organoids were less susceptible to γδ T cell-mediated cytotoxicity compared to HPV-transformed organoids and cancerous organoids. To identify the underlying pathways involved in this observed cytotoxicity, we performed bulk-RNA sequencing on the organoid lines, revealing differences in DNA-damage and cell cycle checkpoint pathways, as well as transcription of potential γδ T cell ligands. We validated these results using immunoblotting and flow cytometry. We also demonstrated the involvement of BTN3A1 and BTN2A1, crucial molecules for γδ T cell activation, as well as differential expression of PDL1/CD274 in cancer, E6/E7+ and healthy organoids. Interestingly, we observed a significant reduction in cytotoxicity upon blocking MSH2, a protein involved in DNA mismatch-repair. In summary, we established a co-culture system of γδ T cells with cervical cancer organoids, providing a novel in vitro model to optimize innovative patient-specific immunotherapies for cervical cancer.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1281646/fullcervical cancerhuman papillomavirusectocervixorganoidsimmunotherapyγδ T cells |
| spellingShingle | Junxue Dong Junxue Dong David Holthaus Christian Peters Stefanie Koster Marzieh Ehsani Alvaro Quevedo-Olmos Hilmar Berger Hilmar Berger Michal Zarobkiewicz Michal Zarobkiewicz Mandy Mangler Mandy Mangler Rajendra Kumar Gurumurthy Nina Hedemann Cindrilla Chumduri Cindrilla Chumduri Cindrilla Chumduri Dieter Kabelitz Thomas F. Meyer Thomas F. Meyer γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoids Frontiers in Immunology cervical cancer human papillomavirus ectocervix organoids immunotherapy γδ T cells |
| title | γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoids |
| title_full | γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoids |
| title_fullStr | γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoids |
| title_full_unstemmed | γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoids |
| title_short | γδ T cell-mediated cytotoxicity against patient-derived healthy and cancer cervical organoids |
| title_sort | γδ t cell mediated cytotoxicity against patient derived healthy and cancer cervical organoids |
| topic | cervical cancer human papillomavirus ectocervix organoids immunotherapy γδ T cells |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1281646/full |
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