1. Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer.
- Author
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Kandala S, Ramos M, Voith von Voithenberg L, Diaz-Jimenez A, Chocarro S, Keding J, Brors B, Imbusch CD, and Sotillo R
- Subjects
- Humans, Animals, Mice, Cell Line, Tumor, Receptor, ErbB-2 genetics, NF-kappa B metabolism, B7-H1 Antigen metabolism, Mannose Receptor metabolism, Killer Cells, Natural immunology, Heterografts, MCF-7 Cells, Female, Chromosomal Instability, Breast Neoplasms genetics, Breast Neoplasms immunology, Immune Tolerance, Polo-Like Kinase 1 genetics, Polo-Like Kinase 1 metabolism, Tumor Escape
- Abstract
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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2023
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