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Abstract
Chromosomal instability (CIN), the failure of cells to segregate chromosomes correctly during cell division, is a typical feature of solid and hematopoietic tumors. By fostering intratumor heterogeneity and facilitating therapy resistance CIN aids in the growth of tumors. Natural killer (NK) cells have been shown to recognize and destroy cells with complex karyotypes in in vitro experiments. Contrarily, immunosuppressive phenotype has also been noted in human malignancies with high levels of CIN. However, which CIN-associated genetic characteristics influence immune recognition during tumor progression still remains to be elucidated. Previous research from our group demonstrated that overexpression of Polo-like kinase 1 (Plk1) in Her2- positive mammary tumors, resulted in increased CIN levels along with a delay in tumor initiation. Using the same mouse model, I demonstrate that Her2-Plk1 tumors induce a senescence-associated secretory phenotype (SASP) and mediate immune evasion by upregulating PD-L1 and CD206 and inducing non-cell-autonomous NF-kB signaling (RELB). Immune cells from early-stage induced mammary glands were sequenced and the results disclosed the presence of Arg1+ macrophages with EMT signatures, NK cells (CD11b–CD27+) with reduced effector capabilities along with increased infiltration of resting regulatory T cells during development of Her2-Plk1 tumors compared to tumors with low CIN. Thus, immune modulation in tumors possessing high CIN happens very early during tumor development with multiple arms of the immune system playing an important role. We further corroborate similar findings in human breast tumors expressing high levels of PLK1 and find upregulation of gene sets associated with SASP, NF-kB signaling and immune suppression. In conclusion, the results presented from in vivo experiments aid in understanding the interaction between different levels of CIN and the immune system. The study also highlights the need for novel adjuvant therapies such as anti-PDL1 or RELB inhibition in the context of chromosomally unstable tumors expressing PLK1
Document type: | Dissertation |
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Supervisor: | Sotillo, Prof. Dr. Rocio |
Place of Publication: | Heidelberg |
Date of thesis defense: | 24 January 2023 |
Date Deposited: | 20 Apr 2023 08:30 |
Date: | 2023 |
Faculties / Institutes: | The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences |
DDC-classification: | 570 Life sciences |