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@ARTICLE{Pane:241139,
author = {A. Pane$^*$ and T. Kordaß$^*$ and A. Hotz-Wagenblatt$^*$
and E. Dickes$^*$ and A. Kopp-Schneider$^*$ and R. Will$^*$
and B. Seliger and W. Osen$^*$ and S. Eichmüller$^*$},
title = {{M}icro{RNA}s affecting the susceptibility of melanoma
cells to {CD}8+ {T} cell-mediated cytolysis.},
journal = {Clinical and translational medicine},
volume = {13},
number = {2},
issn = {2001-1326},
address = {Hoboken, NJ},
publisher = {Wiley},
reportid = {DKFZ-2023-00252},
pages = {e1186},
year = {2023},
note = {#EA:D210#LA:D210#},
abstract = {The regulatory functions of microRNAs (miRNAs) in
anti-tumour immunity have been mainly described in immune
effector cells. Since little is known about miRNA effects on
the susceptibility of target cells during T cell-target cell
interaction, this study focused on the identification of
miRNAs expressed in tumour cells controlling their
susceptibility to CD8+ T cell-mediated
cytotoxicity.Luciferase expressing B16F10 melanoma (B16F10
Luci+ ) cells transfected with individual miRNAs covering a
comprehensive murine miRNA library were screened for their
susceptibility to lysis by an established cytotoxic T
lymphocyte (CTL) line (5a, clone Nβ) specific for the
melanoma-associated antigen tyrosinase-related protein 2.
miRNAs with the most pronounced effects on T cell-mediated
lysis were validated and stably expressed in B16F10 cells.
In silico analyses identified common targets of miRNA sets
determined by the screen, which were further confirmed by
small interfering RNA (siRNA)-mediated silencing experiments
modulating immune surveillance. The Ingenuity Pathway
Analysis (IPA) software and RNA sequencing (RNA-seq) data
from miRNA-overexpressing cell lines were applied to
investigate the underlying mechanisms. The Cancer Genome
Atlas (TCGA)-derived miRNA sequencing data were used to
assess the correlation of miRNA expression with melanoma
patients' survival.The miRNA screen resulted in the
selection of seven miRNAs enhancing CTL-mediated melanoma
cell killing in vitro. Upon stable overexpression of
selected miRNAs, hsa-miR-320a-3p, mmu-miR-7037-5p and
mmu-miR-666-3p were determined as most effective in
enhancing susceptibility to CTL lysis. In silico analyses
and subsequent siRNA-mediated silencing experiments
identified Psmc3 and Ndufa1 as common miRNA targets possibly
involved in the functional effects observed. The analyses of
RNA-seq data with IPA showed pathways, networks, biological
functions and key molecules potentially involved in the
miRNA-mediated functional effects. Finally, based on TCGA
data analysis, a positive correlation of the conserved
miRNAs among the panel of the seven identified miRNAs with
overall survival of melanoma patients was determined.For the
first time, this study uncovered miRNA species that affect
the susceptibility of melanoma cells to T cell-mediated
killing. These miRNAs might represent attractive candidates
for novel therapy approaches against melanoma and other
tumour entities.},
keywords = {Humans / Animals / Mice / MicroRNAs: genetics / MicroRNAs:
metabolism / Melanoma: genetics / RNA, Small Interfering /
CD8-Positive T-Lymphocytes: metabolism / Ndufa1 (Other) /
Psmc3 (Other) / cytotoxic T lymphocyte (CTL) (Other) /
melanoma (Other) / miRNA (Other) / screening (Other) /
MicroRNAs (NLM Chemicals) / RNA, Small Interfering (NLM
Chemicals)},
cin = {D210 / W610 / C060 / W111},
ddc = {610},
cid = {I:(DE-He78)D210-20160331 / I:(DE-He78)W610-20160331 /
I:(DE-He78)C060-20160331 / I:(DE-He78)W111-20160331},
pnm = {314 - Immunologie und Krebs (POF4-314)},
pid = {G:(DE-HGF)POF4-314},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:36718025},
doi = {10.1002/ctm2.1186},
url = {https://inrepo02.dkfz.de/record/241139},
}