eprintid: 33160
rev_number: 12
eprint_status: archive
userid: 7327
dir: disk0/00/03/31/60
datestamp: 2023-04-20 08:30:40
lastmod: 2023-05-03 12:25:19
status_changed: 2023-04-20 08:30:40
type: doctoralThesis
metadata_visibility: show
creators_name: Kandala, Sridhar
title: Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer
subjects: ddc-570
divisions: i-140001
adv_faculty: af-14
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
date: 2023
id_scheme: DOI
id_number: 10.11588/heidok.00033160
ppn_swb: 184448680X
own_urn: urn:nbn:de:bsz:16-heidok-331602
date_accepted: 2023-01-24
advisor: HASH(0x559de7921288)
language: eng
bibsort: KANDALASRICHRONICCHR2023
full_text_status: public
place_of_pub: Heidelberg
citation:   Kandala, Sridhar  (2023) Chronic chromosome instability induced by Plk1 results in immune suppression in breast cancer.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/33160/1/Sridhar_thesis.pdf