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Cytokine-Induced Killer Cells Kill Chemo-surviving Melanoma Cancer Stem Cells
Ist Teil von
Clinical cancer research, 2017-05, Vol.23 (9), p.2277-2288
Ort / Verlag
United States: American Association for Cancer Research Inc
Erscheinungsjahr
2017
Quelle
MEDLINE
Beschreibungen/Notizen
The MHC-unrestricted activity of cytokine-induced killer (CIK) cells against chemo-surviving melanoma cancer stem cells (mCSC) was explored, as CSCs are considered responsible for chemoresistance and relapses.
Putative mCSCs were visualized by engineering patient-derived melanoma cells (MC) with a lentiviral vector encoding eGFP under expression control by stemness gene promoter
Their stemness potential was confirmed
by limiting dilution assays. We explored the sensitivity of eGFP
mCSCs to chemotherapy (CHT), BRAF inhibitor (BRAFi) or CIK cells, as single agents or in sequence,
First, we treated MCs
with fotemustine or dabrafenib (BRAF-mutated cases); then, surviving MCs, enriched in mCSCs, were challenged with autologous CIK cells. CIK cell activity against chemoresistant mCSCs was confirmed
in two distinct immunodeficient murine models.
We visualized eGFP
mCSCs (14% ± 2.1%) in 11 MCs. The tumorigenic precursor rate
was higher within eGFP
MCs (1/42) compared with the eGFP
counterpart (1/4,870).
mCSCs were relatively resistant to CHT and BRAFi, but killed by CIK cells (
= 11, 8/11 autologous), with specific lysis ranging from 95% [effector:tumor ratio (E:T), 40:1] to 20% (E:T 1:3).
infusion of autologous CIK cells into mice bearing xenografts from three distinct melanomas demonstrated significant tumor responses involving CHT-spared eGFP
mCSCs (
= 0.001). Sequential CHT-immunotherapy treatment retained antitumor activity (
= 12,
= 0.001) reducing mCSC rates (
= 0.01).
These findings are the first demonstration that immunotherapy with CIK cells is active against autologous mCSCs surviving CHT or BRAFi. An experimental platform for mCSC study and rationale for CIK cells in melanoma clinical study is provided.
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