Chemotherapy-induced apoptosis, autophagy and cell cycle arrest are key drivers of synergy in chemo-immunotherapy of epithelial ovarian cancer

Cancer Immunology, Immunotherapy : CII
John WahbaSadaf Ghaem-Maghami

Abstract

Epithelial ovarian cancer (EOC) is the most lethal of all gynecological malignancies in the UK. Recent evidence has shown that there is potential for immunotherapies to be successful in treating this cancer. We have previously shown the effective application of combinations of traditional chemotherapy and CAR (chimeric antigen receptor) T cell immunotherapy in in vitro and in vivo models of EOC. Platinum-based chemotherapy synergizes with ErbB-targeted CAR T cells (named T4), significantly reducing tumor burden in mice. Here, we show that paclitaxel synergizes with T4 as well, and look into the mechanisms behind the effectiveness of chemo-immunotherapy in our system. Impairment of caspase activity using pan-caspase inhibitor Z-VAD reveals this chemotherapy-induced apoptotic pathway as an essential factor in driving synergy. Mannose-6-phosphate receptor-mediated autophagy and the arrest of cell cycle in G2/M are also shown to be induced by chemotherapy and significantly contributing to the synergy. Increased expression of PD-1 on T4 CAR T cells occurred when these were in culture with ovarian tumor cells; on the other hand, EOC cell lines showed increased PD-L1 expression following chemotherapy treatment. These findings provided...Continue Reading

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Citations

Mar 26, 2020·International Journal of Cancer. Journal International Du Cancer·Yueqing GongJunjie Wang
Mar 23, 2020·Cancer Immunology, Immunotherapy : CII·Marina NatoliYumeng Mao
Apr 4, 2021·International Journal of Molecular Sciences·Katarzyna M TerlikowskaSławomir J Terlikowski
Feb 17, 2020·NAR Cancer·Christian BaillyBruno Quesnel

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Methods Mentioned

BETA
PCR
flow cytometry
Flow
xenografts

Software Mentioned

Living Image
Graphpad Prism
FlowJo
CellQuest Pro
Softmax Pro
OPTIMA

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