Low-dose chemotherapy combined with NK cell-based immunotherapy as a treatment for triple negative breast cancer

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Idri, S., 2019. Low-dose chemotherapy combined with NK cell-based immunotherapy as a treatment for triple negative breast cancer. PhD, Nottingham Trent University.

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Abstract

Despite considerable progress and the emerging use of immunotherapies, chemotherapy remains the only routine clinical option for treating triple negative breast cancer (TNBC). However, this is associated with severe toxicity, is not effective in all patients and chemo-resistance can develop. NK cells are emerging as powerful tools for cancer immunotherapy and we hypothesised that NK cell-based therapies could be improved by combining them with other approaches that modify various components of the tumour and its environment and renders tumours more sensitive to NK cell cytotoxicity.

In addition to being less toxic and having a lower impact on a patient’s quality of life, evidence suggests that low-dose metronomic chemotherapy modulates adaptive and innate anti-tumour immune responses. Accordingly, the aim of this study was to enhance anti-tumour activity of adoptively transferred NK-cells using low-dose metronomic chemotherapy.

Herein, the effect of treatment with low-dose doxorubicin on the phenotype of human breast cancer cell lines corresponding to different molecular subtypes of disease [MCF-7 (Luminal A); SK-BR-3 (Her2+); MDA-MB-468 (Triple Negative); MDA-MB-231/RFP/LUC (Triple Negative)] and their sensitivity to NK cell killing was investigated, as was the capacity of combining low-dose doxorubicin and adoptive NK cell transfer to control the growth and metastasis of human MDA-MB-231 xenografts in immunedeficient mice.

We demonstrate that low-dose doxorubicin treatment halts the proliferation of breast cancer cells and triggers expression of natural killer (NK) cell ligands, enhances sensitivity to NK cell-mediated cytotoxicity in vitro and modulates important cancer pathways associated with invasion and metastasis. In vivo, the combination of low-dose doxorubicin with adoptive transfer of IL-2 activated human NK cells, reduced the growth of MDA-MB-231 cell-derived tumours in a pre-clinical murine xenograft model.

These findings confirmed the capacity of low-dose chemotherapy to sensitise tumours to NK cell cytotoxicity and indicated the therapeutic potential of combining low-dose chemotherapy and NK cell therapy for the treatment of patients with TNBC, for whom current therapies are largely ineffective.

Item Type:	Thesis
Creators:	Idri, S.
Date:	September 2019
Rights:	This work is the intellectual property of the author. You may copy up to 5 % of the work for private study, or personal, non-commercial research. Any re-use of the information contained within this document should be fully referenced, quoting the author, title, university, degree level and pagination. Queries or requests for any other use, or if a more substantial copy is required, should be directed in the owner(s) of the Intellectual Property Rights.
Divisions:	Schools > School of Science and Technology
Record created by:	Linda Sullivan
Date Added:	07 Apr 2021 13:42
Last Modified:	31 May 2021 15:04
URI:	https://irep.ntu.ac.uk/id/eprint/42656