Short-term immune-checkpoint inhibition partially rescues perturbed bone marrow hematopoiesis in mismatch-repair deficient tumors
Wide-spread cancer-related immunosuppression often curtails immune-mediated antitumoral responses. Immune-checkpoint inhibitors (ICIs) have become a state-of-the-art treatment modality for mismatch repair-deficient (dMMR) tumors. Still, the impact of ICI-treatment on bone marrow perturbations is lar...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2230669 |
| _version_ | 1826914932587757568 |
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| author | Paula Krone Annabell Wolff Julia Teichmann Johanna Maennicke Julia Henne Leonie Engster Inken Salewski Wendy Bergmann Christian Junghanss Claudia Maletzki |
| author_facet | Paula Krone Annabell Wolff Julia Teichmann Johanna Maennicke Julia Henne Leonie Engster Inken Salewski Wendy Bergmann Christian Junghanss Claudia Maletzki |
| author_sort | Paula Krone |
| collection | DOAJ |
| description | Wide-spread cancer-related immunosuppression often curtails immune-mediated antitumoral responses. Immune-checkpoint inhibitors (ICIs) have become a state-of-the-art treatment modality for mismatch repair-deficient (dMMR) tumors. Still, the impact of ICI-treatment on bone marrow perturbations is largely unknown. Using anti-PD1 and anti-LAG-3 ICI treatments, we here investigated the effect of bone marrow hematopoiesis in tumor-bearing Msh2loxP/loxP;TgTg(Vil1-cre) mice. The OS under anti-PD1 antibody treatment was 7.0 weeks (vs. 3.3 weeks and 5.0 weeks, control and isotype, respectively). In the anti-LAG-3 antibody group, OS was 13.3 weeks and thus even longer than in the anti-PD1 group (p = 0.13). Both ICIs induced a stable disease and reduced circulating and splenic regulatory T cells. In the bone marrow, a perturbed hematopoiesis was identified in tumor-bearing control mice, which was partially rescued by ICI treatment. In particular, B cell precursors and innate lymphoid progenitors were significantly increased upon anti-LAG-3 therapy to levels seen in tumor-free control mice. Additional normalizing effects of ICI treatment were observed for lin−c-Kit+IRF8+ hematopoietic stem cells, which function as a “master” negative regulator of the formation of polymorphonuclear-myeloid-derived suppressor cell generation. Accompanying immunofluorescence on the TME revealed significantly reduced numbers of CD206+F4/80+ and CD163+ tumor-associated M2 macrophages and CD11b+Gr1+ myeloid-derived suppressor cells especially upon anti-LAG-3 treatment. This study confirms the perturbed hematopoiesis in solid cancer. Anti-LAG-3 treatment partially restores normal hematopoiesis. The interference of anti-LAG-3 with suppressor cell populations in otherwise inaccessible niches renders this ICI very promising for subsequent clinical application. |
| first_indexed | 2024-03-08T17:12:53Z |
| format | Article |
| id | doaj.art-74275ddb60e74d7fb08e87f87a7b42d8 |
| institution | Directory Open Access Journal |
| issn | 2162-402X |
| language | English |
| last_indexed | 2025-02-17T11:52:18Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
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| series | OncoImmunology |
| spelling | doaj.art-74275ddb60e74d7fb08e87f87a7b42d82024-12-27T17:34:38ZengTaylor & Francis GroupOncoImmunology2162-402X2023-12-0112110.1080/2162402X.2023.2230669Short-term immune-checkpoint inhibition partially rescues perturbed bone marrow hematopoiesis in mismatch-repair deficient tumorsPaula Krone0Annabell Wolff1Julia Teichmann2Johanna Maennicke3Julia Henne4Leonie Engster5Inken Salewski6Wendy Bergmann7Christian Junghanss8Claudia Maletzki9Department of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, GermanyCore Facility for Cell Sorting & Cell Analysis, Laboratory for Clinical Immunology, Rostock University Medical Center, Rostock, GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, GermanyDepartment of Medicine, Clinic III – Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, Rostock, GermanyWide-spread cancer-related immunosuppression often curtails immune-mediated antitumoral responses. Immune-checkpoint inhibitors (ICIs) have become a state-of-the-art treatment modality for mismatch repair-deficient (dMMR) tumors. Still, the impact of ICI-treatment on bone marrow perturbations is largely unknown. Using anti-PD1 and anti-LAG-3 ICI treatments, we here investigated the effect of bone marrow hematopoiesis in tumor-bearing Msh2loxP/loxP;TgTg(Vil1-cre) mice. The OS under anti-PD1 antibody treatment was 7.0 weeks (vs. 3.3 weeks and 5.0 weeks, control and isotype, respectively). In the anti-LAG-3 antibody group, OS was 13.3 weeks and thus even longer than in the anti-PD1 group (p = 0.13). Both ICIs induced a stable disease and reduced circulating and splenic regulatory T cells. In the bone marrow, a perturbed hematopoiesis was identified in tumor-bearing control mice, which was partially rescued by ICI treatment. In particular, B cell precursors and innate lymphoid progenitors were significantly increased upon anti-LAG-3 therapy to levels seen in tumor-free control mice. Additional normalizing effects of ICI treatment were observed for lin−c-Kit+IRF8+ hematopoietic stem cells, which function as a “master” negative regulator of the formation of polymorphonuclear-myeloid-derived suppressor cell generation. Accompanying immunofluorescence on the TME revealed significantly reduced numbers of CD206+F4/80+ and CD163+ tumor-associated M2 macrophages and CD11b+Gr1+ myeloid-derived suppressor cells especially upon anti-LAG-3 treatment. This study confirms the perturbed hematopoiesis in solid cancer. Anti-LAG-3 treatment partially restores normal hematopoiesis. The interference of anti-LAG-3 with suppressor cell populations in otherwise inaccessible niches renders this ICI very promising for subsequent clinical application.https://www.tandfonline.com/doi/10.1080/2162402X.2023.2230669Hematopoietic progenitor cellhypermutated tumorimmunotherapytumor microenvironment |
| spellingShingle | Paula Krone Annabell Wolff Julia Teichmann Johanna Maennicke Julia Henne Leonie Engster Inken Salewski Wendy Bergmann Christian Junghanss Claudia Maletzki Short-term immune-checkpoint inhibition partially rescues perturbed bone marrow hematopoiesis in mismatch-repair deficient tumors OncoImmunology Hematopoietic progenitor cell hypermutated tumor immunotherapy tumor microenvironment |
| title | Short-term immune-checkpoint inhibition partially rescues perturbed bone marrow hematopoiesis in mismatch-repair deficient tumors |
| title_full | Short-term immune-checkpoint inhibition partially rescues perturbed bone marrow hematopoiesis in mismatch-repair deficient tumors |
| title_fullStr | Short-term immune-checkpoint inhibition partially rescues perturbed bone marrow hematopoiesis in mismatch-repair deficient tumors |
| title_full_unstemmed | Short-term immune-checkpoint inhibition partially rescues perturbed bone marrow hematopoiesis in mismatch-repair deficient tumors |
| title_short | Short-term immune-checkpoint inhibition partially rescues perturbed bone marrow hematopoiesis in mismatch-repair deficient tumors |
| title_sort | short term immune checkpoint inhibition partially rescues perturbed bone marrow hematopoiesis in mismatch repair deficient tumors |
| topic | Hematopoietic progenitor cell hypermutated tumor immunotherapy tumor microenvironment |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2023.2230669 |
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