Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer
Summary: Chromosome instability (CIN) contributes to resistance to therapies and tumor evolution. Although natural killer (NK) cells can eliminate cells with complex karyotypes, high-CIN human tumors have an immunosuppressive phenotype. To understand which CIN-associated molecular features alter imm...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723012780 |
| _version_ | 1797598007434149888 |
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| author | Sridhar Kandala Maria Ramos Lena Voith von Voithenberg Alberto Diaz-Jimenez Sara Chocarro Johanna Keding Benedikt Brors Charles D. Imbusch Rocio Sotillo |
| author_facet | Sridhar Kandala Maria Ramos Lena Voith von Voithenberg Alberto Diaz-Jimenez Sara Chocarro Johanna Keding Benedikt Brors Charles D. Imbusch Rocio Sotillo |
| author_sort | Sridhar Kandala |
| collection | DOAJ |
| description | Summary: Chromosome instability (CIN) contributes to resistance to therapies and tumor evolution. Although natural killer (NK) cells can eliminate cells with complex karyotypes, high-CIN human tumors have an immunosuppressive phenotype. To understand which CIN-associated molecular features alter immune recognition during tumor evolution, we overexpress Polo-like kinase 1 (Plk1) in a Her2+ breast cancer model. These high-CIN tumors activate a senescence-associated secretory phenotype (SASP), upregulate PD-L1 and CD206, and induce non-cell-autonomous nuclear factor κB (NF-κβ) signaling, facilitating immune evasion. Single-cell RNA sequencing from pre-neoplastic mammary glands unveiled the presence of Arg1+ macrophages, NK cells with reduced effector functions, and increased resting regulatory T cell infiltration. We further show that high PLK1-expressing human breast tumors display gene expression patterns associated with SASP, NF-κβ signaling, and immune suppression. These findings underscore the need to understand the immune landscape in CIN tumors to identify more effective therapies, potentially combining immune checkpoint or NF-κβ inhibitors with current treatments. |
| first_indexed | 2024-03-11T03:13:18Z |
| format | Article |
| id | doaj.art-478d76bd7d014ba4b60441bc8b5a3250 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-11T03:13:18Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-478d76bd7d014ba4b60441bc8b5a32502023-11-18T04:28:32ZengElsevierCell Reports2211-12472023-12-014212113266Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancerSridhar Kandala0Maria Ramos1Lena Voith von Voithenberg2Alberto Diaz-Jimenez3Sara Chocarro4Johanna Keding5Benedikt Brors6Charles D. Imbusch7Rocio Sotillo8Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, GermanyDivision of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, GermanyDivision of Applied Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, GermanyDivision of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, GermanyDivision of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, GermanyDivision of Applied Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, GermanyDivision of Applied Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Medical Oncology, National Center for Tumor Diseases, Heidelberg University Hospital, 69120 Heidelberg, GermanyDivision of Applied Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, GermanyDivision of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Translational Lung Research Center Heidelberg (TRLC), German Center for Lung Research (DZL), Heidelberg, Germany; Corresponding authorSummary: Chromosome instability (CIN) contributes to resistance to therapies and tumor evolution. Although natural killer (NK) cells can eliminate cells with complex karyotypes, high-CIN human tumors have an immunosuppressive phenotype. To understand which CIN-associated molecular features alter immune recognition during tumor evolution, we overexpress Polo-like kinase 1 (Plk1) in a Her2+ breast cancer model. These high-CIN tumors activate a senescence-associated secretory phenotype (SASP), upregulate PD-L1 and CD206, and induce non-cell-autonomous nuclear factor κB (NF-κβ) signaling, facilitating immune evasion. Single-cell RNA sequencing from pre-neoplastic mammary glands unveiled the presence of Arg1+ macrophages, NK cells with reduced effector functions, and increased resting regulatory T cell infiltration. We further show that high PLK1-expressing human breast tumors display gene expression patterns associated with SASP, NF-κβ signaling, and immune suppression. These findings underscore the need to understand the immune landscape in CIN tumors to identify more effective therapies, potentially combining immune checkpoint or NF-κβ inhibitors with current treatments.http://www.sciencedirect.com/science/article/pii/S2211124723012780CP: CancerCP: Cell biology |
| spellingShingle | Sridhar Kandala Maria Ramos Lena Voith von Voithenberg Alberto Diaz-Jimenez Sara Chocarro Johanna Keding Benedikt Brors Charles D. Imbusch Rocio Sotillo Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer Cell Reports CP: Cancer CP: Cell biology |
| title | Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer |
| title_full | Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer |
| title_fullStr | Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer |
| title_full_unstemmed | Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer |
| title_short | Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer |
| title_sort | chronic chromosome instability induced by plk1 results in immune suppression in breast cancer |
| topic | CP: Cancer CP: Cell biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723012780 |
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