title: Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer
creator: Kandala, Sridhar
subject: ddc-570
subject: 570 Life sciences
description: 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
date: 2023
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserver/33160/1/Sridhar_thesis.pdf
identifier: DOI:10.11588/heidok.00033160
identifier: urn:nbn:de:bsz:16-heidok-331602
identifier:   Kandala, Sridhar  (2023) Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/33160/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng