Human CD22-Transgenic, Primary Murine Lymphoma Challenges Immunotherapies in Organ-Specific Tumor Microenvironments
Targeted immunotherapies have greatly changed treatment of patients with B cell malignancies. To further enhance immunotherapies, research increasingly focuses on the tumor microenvironment (TME), which differs considerably by organ site. However, immunocompetent mouse models of disease to study imm...
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| Format: | Article |
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MDPI AG
2021-09-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/19/10433 |
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| author | Franziska Gsottberger Carolin Brandl Kerstin Wendland Srdjan Petkovic Charlotte Emmerich Ramona Erber Carol Geppert Arndt Hartmann Andreas Mackensen Lars Nitschke Fabian Müller |
| author_facet | Franziska Gsottberger Carolin Brandl Kerstin Wendland Srdjan Petkovic Charlotte Emmerich Ramona Erber Carol Geppert Arndt Hartmann Andreas Mackensen Lars Nitschke Fabian Müller |
| author_sort | Franziska Gsottberger |
| collection | DOAJ |
| description | Targeted immunotherapies have greatly changed treatment of patients with B cell malignancies. To further enhance immunotherapies, research increasingly focuses on the tumor microenvironment (TME), which differs considerably by organ site. However, immunocompetent mouse models of disease to study immunotherapies targeting human molecules within organ-specific TME are surprisingly rare. We developed a <i>myc</i>-driven, primary murine lymphoma model expressing a human-mouse chimeric CD22 (h/mCD22). Stable engraftment of three distinct h/mCD22<sup>+</sup> lymphoma was established after subcutaneous and systemic injection. However, only systemic lymphoma showed immune infiltration that reflected human disease. In this model, myeloid cells supported lymphoma growth and showed a phenotype of myeloid-derived suppressor cells. The human CD22-targeted immunotoxin Moxetumomab was highly active against h/mCD22<sup>+</sup> lymphoma and similarly reduced infiltration of bone marrow and spleen of all three models up to 90-fold while efficacy against lymphoma in lymph nodes varied substantially, highlighting relevance of organ-specific TME. As in human aggressive lymphoma, anti-PD-L1 as monotherapy was not efficient. However, anti-PD-L1 enhanced efficacy of Moxetumomab suggesting potential for future clinical application. The novel model system of h/mCD22<sup>+</sup> lymphoma provides a unique platform to test targeted immunotherapies and may be amenable for other human B cell targets such as CD19 and CD20. |
| first_indexed | 2024-03-10T06:59:36Z |
| format | Article |
| id | doaj.art-251222e66c2d437c94f4453a03535716 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T06:59:36Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-251222e66c2d437c94f4453a035357162023-11-22T16:09:34ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-09-0122191043310.3390/ijms221910433Human CD22-Transgenic, Primary Murine Lymphoma Challenges Immunotherapies in Organ-Specific Tumor MicroenvironmentsFranziska Gsottberger0Carolin Brandl1Kerstin Wendland2Srdjan Petkovic3Charlotte Emmerich4Ramona Erber5Carol Geppert6Arndt Hartmann7Andreas Mackensen8Lars Nitschke9Fabian Müller10Department of Internal Medicine 5, Haematology and Oncology, University Hospital of Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg (FAU), 91054 Erlangen, GermanyDepartment of Biology, Friedrich-Alexander University of Erlangen-Nuremberg (FAU), 91054 Erlangen, GermanyDepartment of Internal Medicine 5, Haematology and Oncology, University Hospital of Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg (FAU), 91054 Erlangen, GermanyDepartment of Internal Medicine 5, Haematology and Oncology, University Hospital of Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg (FAU), 91054 Erlangen, GermanyDepartment of Internal Medicine 5, Haematology and Oncology, University Hospital of Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg (FAU), 91054 Erlangen, GermanyDepartment of Pathology, University Hospital of Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg (FAU), 91054 Erlangen, GermanyDepartment of Pathology, University Hospital of Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg (FAU), 91054 Erlangen, GermanyDepartment of Pathology, University Hospital of Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg (FAU), 91054 Erlangen, GermanyDepartment of Internal Medicine 5, Haematology and Oncology, University Hospital of Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg (FAU), 91054 Erlangen, GermanyDepartment of Biology, Friedrich-Alexander University of Erlangen-Nuremberg (FAU), 91054 Erlangen, GermanyDepartment of Internal Medicine 5, Haematology and Oncology, University Hospital of Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg (FAU), 91054 Erlangen, GermanyTargeted immunotherapies have greatly changed treatment of patients with B cell malignancies. To further enhance immunotherapies, research increasingly focuses on the tumor microenvironment (TME), which differs considerably by organ site. However, immunocompetent mouse models of disease to study immunotherapies targeting human molecules within organ-specific TME are surprisingly rare. We developed a <i>myc</i>-driven, primary murine lymphoma model expressing a human-mouse chimeric CD22 (h/mCD22). Stable engraftment of three distinct h/mCD22<sup>+</sup> lymphoma was established after subcutaneous and systemic injection. However, only systemic lymphoma showed immune infiltration that reflected human disease. In this model, myeloid cells supported lymphoma growth and showed a phenotype of myeloid-derived suppressor cells. The human CD22-targeted immunotoxin Moxetumomab was highly active against h/mCD22<sup>+</sup> lymphoma and similarly reduced infiltration of bone marrow and spleen of all three models up to 90-fold while efficacy against lymphoma in lymph nodes varied substantially, highlighting relevance of organ-specific TME. As in human aggressive lymphoma, anti-PD-L1 as monotherapy was not efficient. However, anti-PD-L1 enhanced efficacy of Moxetumomab suggesting potential for future clinical application. The novel model system of h/mCD22<sup>+</sup> lymphoma provides a unique platform to test targeted immunotherapies and may be amenable for other human B cell targets such as CD19 and CD20.https://www.mdpi.com/1422-0067/22/19/10433<i>myc</i>-driven lymphomamouse modellymphoma microenvironmenttumor microenvironmentCD22immunotoxin |
| spellingShingle | Franziska Gsottberger Carolin Brandl Kerstin Wendland Srdjan Petkovic Charlotte Emmerich Ramona Erber Carol Geppert Arndt Hartmann Andreas Mackensen Lars Nitschke Fabian Müller Human CD22-Transgenic, Primary Murine Lymphoma Challenges Immunotherapies in Organ-Specific Tumor Microenvironments International Journal of Molecular Sciences <i>myc</i>-driven lymphoma mouse model lymphoma microenvironment tumor microenvironment CD22 immunotoxin |
| title | Human CD22-Transgenic, Primary Murine Lymphoma Challenges Immunotherapies in Organ-Specific Tumor Microenvironments |
| title_full | Human CD22-Transgenic, Primary Murine Lymphoma Challenges Immunotherapies in Organ-Specific Tumor Microenvironments |
| title_fullStr | Human CD22-Transgenic, Primary Murine Lymphoma Challenges Immunotherapies in Organ-Specific Tumor Microenvironments |
| title_full_unstemmed | Human CD22-Transgenic, Primary Murine Lymphoma Challenges Immunotherapies in Organ-Specific Tumor Microenvironments |
| title_short | Human CD22-Transgenic, Primary Murine Lymphoma Challenges Immunotherapies in Organ-Specific Tumor Microenvironments |
| title_sort | human cd22 transgenic primary murine lymphoma challenges immunotherapies in organ specific tumor microenvironments |
| topic | <i>myc</i>-driven lymphoma mouse model lymphoma microenvironment tumor microenvironment CD22 immunotoxin |
| url | https://www.mdpi.com/1422-0067/22/19/10433 |
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