CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors
Mismatch repair-deficient (dMMR) tumors show a good response toward immune checkpoint inhibitors (ICI), but developing resistance impairs patients’ outcomes. Here, we compared the therapeutic potential of an α-PD-L1 antibody with the CDK4/6 inhibitor abemaciclib in two preclinical mouse models of dM...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2022-12-01
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| Series: | OncoImmunology |
| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2094583 |
| _version_ | 1818108368588374016 |
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| author | Inken Salewski Julia Henne Leonie Engster Paula Krone Bjoern Schneider Caterina Redwanz Heiko Lemcke Larissa Henze Christian Junghanss Claudia Maletzki |
| author_facet | Inken Salewski Julia Henne Leonie Engster Paula Krone Bjoern Schneider Caterina Redwanz Heiko Lemcke Larissa Henze Christian Junghanss Claudia Maletzki |
| author_sort | Inken Salewski |
| collection | DOAJ |
| description | Mismatch repair-deficient (dMMR) tumors show a good response toward immune checkpoint inhibitors (ICI), but developing resistance impairs patients’ outcomes. Here, we compared the therapeutic potential of an α-PD-L1 antibody with the CDK4/6 inhibitor abemaciclib in two preclinical mouse models of dMMR cancer, focusing on immune-modulatory effects of either treatment. Abemaciclib monotherapy significantly prolonged overall survival of Mlh1−/− and Msh2loxP/loxP;TgTg(Vil1-cre) mice (Mlh1−/−: 14.5 wks vs. 9.0 wks (α-PD-L1), and 3.5 wks (control); Msh2loxP/loxP;TgTg(Vil1-cre): 11.7 wks vs. 9.6 wks (α-PD-L1), and 2.0 wks (control)). The combination was not superior to either monotherapy. PET/CT imaging revealed individual response profiles, with best clinical responses seen with abemaciclib mono- and combination therapy. Therapeutic effects were accompanied by increasing numbers of tumor-infiltrating CD4+/CD8+ T-cells and lower numbers of M2-macrophages. Levels of T cell exhaustion markers and regulatory T cell counts declined. Expression analysis identified higher numbers of dendritic cells and neutrophils within tumors together with high expression of DNA damage repair genes as part of the global stress response. In Mlh1−/− tumors, abemaciclib suppressed the PI3K/Akt pathway and led to induction of Mxd4/Myc. The immune-modulatory potential of abemaciclib renders this compound ideal for dMMR patients not eligible for ICI treatment. |
| first_indexed | 2024-12-11T02:14:15Z |
| format | Article |
| id | doaj.art-3e095849514f4debaf0bafdf03f37cc7 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2024-12-11T02:14:15Z |
| publishDate | 2022-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj.art-3e095849514f4debaf0bafdf03f37cc72022-12-22T01:24:12ZengTaylor & Francis GroupOncoImmunology2162-402X2022-12-0111110.1080/2162402X.2022.2094583CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumorsInken Salewski0Julia Henne1Leonie Engster2Paula Krone3Bjoern Schneider4Caterina Redwanz5Heiko Lemcke6Larissa Henze7Christian Junghanss8Claudia Maletzki9–Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, University of RostockDepartment of Medicine, Clinic III , Rostock, Germany–Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, University of RostockDepartment of Medicine, Clinic III , Rostock, Germany–Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, University of RostockDepartment of Medicine, Clinic III , Rostock, Germany–Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, University of RostockDepartment of Medicine, Clinic III , Rostock, GermanyInstitute of Pathology, Rostock University Medical Center, University of Rostock, Rostock, GermanyDepartment of Internal Medicine B, Cardiology, University Medicine Greifswald, GermanyDepartment of Cardiac Surgery, Reference and Translation Center for Cardiac Stem Cell Therapy (RTC), Rostock University Medical Center, University of Rostock, Rostock, Germany–Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, University of RostockDepartment of Medicine, Clinic III , Rostock, Germany–Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, University of RostockDepartment of Medicine, Clinic III , Rostock, Germany–Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, University of RostockDepartment of Medicine, Clinic III , Rostock, GermanyMismatch repair-deficient (dMMR) tumors show a good response toward immune checkpoint inhibitors (ICI), but developing resistance impairs patients’ outcomes. Here, we compared the therapeutic potential of an α-PD-L1 antibody with the CDK4/6 inhibitor abemaciclib in two preclinical mouse models of dMMR cancer, focusing on immune-modulatory effects of either treatment. Abemaciclib monotherapy significantly prolonged overall survival of Mlh1−/− and Msh2loxP/loxP;TgTg(Vil1-cre) mice (Mlh1−/−: 14.5 wks vs. 9.0 wks (α-PD-L1), and 3.5 wks (control); Msh2loxP/loxP;TgTg(Vil1-cre): 11.7 wks vs. 9.6 wks (α-PD-L1), and 2.0 wks (control)). The combination was not superior to either monotherapy. PET/CT imaging revealed individual response profiles, with best clinical responses seen with abemaciclib mono- and combination therapy. Therapeutic effects were accompanied by increasing numbers of tumor-infiltrating CD4+/CD8+ T-cells and lower numbers of M2-macrophages. Levels of T cell exhaustion markers and regulatory T cell counts declined. Expression analysis identified higher numbers of dendritic cells and neutrophils within tumors together with high expression of DNA damage repair genes as part of the global stress response. In Mlh1−/− tumors, abemaciclib suppressed the PI3K/Akt pathway and led to induction of Mxd4/Myc. The immune-modulatory potential of abemaciclib renders this compound ideal for dMMR patients not eligible for ICI treatment.https://www.tandfonline.com/doi/10.1080/2162402X.2022.2094583 |
| spellingShingle | Inken Salewski Julia Henne Leonie Engster Paula Krone Bjoern Schneider Caterina Redwanz Heiko Lemcke Larissa Henze Christian Junghanss Claudia Maletzki CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors OncoImmunology |
| title | CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors |
| title_full | CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors |
| title_fullStr | CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors |
| title_full_unstemmed | CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors |
| title_short | CDK4/6 blockade provides an alternative approach for treatment of mismatch-repair deficient tumors |
| title_sort | cdk4 6 blockade provides an alternative approach for treatment of mismatch repair deficient tumors |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2022.2094583 |
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