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Cancer Immunology, Immunotherapy

, Volume 68, Issue 1, pp 131–141 | Cite as

Fighting breast cancer stem cells through the immune-targeting of the xCT cystine–glutamate antiporter

  • Roberto Ruiu
  • Valeria Rolih
  • Elisabetta Bolli
  • Giuseppina Barutello
  • Federica Riccardo
  • Elena Quaglino
  • Irene Fiore Merighi
  • Federica Pericle
  • Gaetano Donofrio
  • Federica Cavallo
  • Laura Conti
Focussed Research Review

Abstract

Tumor relapse and metastatic spreading act as major hindrances to achieve complete cure of breast cancer. Evidence suggests that cancer stem cells (CSC) would function as a reservoir for the local and distant recurrence of the disease, due to their resistance to radio- and chemotherapy and their ability to regenerate the tumor. Therefore, the identification of appropriate molecular targets expressed by CSC may be critical in the development of more effective therapies. Our studies focused on the identification of mammary CSC antigens and on the development of CSC-targeting vaccines. We compared the transcriptional profile of CSC-enriched tumorspheres from an Her2+ breast cancer cell line with that of the more differentiated parental cells. Among the molecules strongly upregulated in tumorspheres we selected the transmembrane amino-acid antiporter xCT. In this review, we summarize the results we obtained with different xCT-targeting vaccines. We show that, despite xCT being a self-antigen, vaccination was able to induce a humoral immune response that delayed primary tumor growth and strongly impaired pulmonary metastasis formation in mice challenged with tumorsphere-derived cells. Moreover, immunotargeting of xCT was able to increase CSC chemosensitivity to doxorubicin, suggesting that it may act as an adjuvant to chemotherapy. In conclusion, our approach based on the comparison of the transcriptome of tumorspheres and parental cells allowed us to identify a novel CSC-related target and to develop preclinical therapeutic approaches able to impact on CSC biology, and therefore, hampering tumor growth and dissemination.

Keywords

Cancer stem cell Vaccine Tumorsphere xCT Breast cancer NIBIT 2017 

Abbreviations

ADCC

Antibody-dependent cell cytotoxicity

ALDH

Aldehyde dehydrogenase

BoHV-4

Bovine herpesvirus-4

CSC

Cancer stem cell

ECD

Extracellular domain

GSH

Glutathione

ROS

Reactive oxygen species

SASP

Sulfasalazine

VLP

Virus-like particles

Notes

Acknowledgements

Not applicable.

Author contributions

Roberto Ruiu, Valeria Rolih, Elisabetta Bolli, and Laura Conti produced the results discussed in this review. Roberto Ruiu, Federica Cavallo and Laura Conti provided major contribution in writing and discussing the manuscript. Federica Pericle provided the VLP technology, Gaetano Donofrio the BoHV-4 technology. Elisabetta Bolli and Valeria Rolih wrote and discussed the sections involving VLP and performed the original ELISA assay reported in this review. Giuseppina Barutello and Federica Riccardo wrote and discussed the sections involving the BALB-neuT model and the translatability of the vaccine. Roberto Ruiu produced the figures. Elena Quaglino, Federica Cavallo, Federica Pericle, Irene Fiore Merighi and Laura Conti critically revised the manuscript. All authors read and approved the final version of the manuscript.

Funding

This paper was supported by a grant from the Italian Association for Cancer Research (IG 11675) to Federica Cavallo.

Compliance with ethical standards

Conflict of interest

The authors declare that no potential conflicts of interest exist.

Ethical approval

All the in vivo experiments were approved by the Italian Ministry of Health, authorization numbers 174/2015-PR, 1042/2016-PR and 500/2017-PR.

Human and animal rights

Mice used for the vaccination experiments reported in this paper were purchased from Charles River Laboratories or bred at the Molecular Biotechnology Center, University of Turin, where all mice were maintained and treated in accordance with the University Ethical Committee and European Union guidelines under Directive 2010/63.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Roberto Ruiu
    • 1
  • Valeria Rolih
    • 1
  • Elisabetta Bolli
    • 1
  • Giuseppina Barutello
    • 1
  • Federica Riccardo
    • 1
  • Elena Quaglino
    • 1
  • Irene Fiore Merighi
    • 1
  • Federica Pericle
    • 2
  • Gaetano Donofrio
    • 3
  • Federica Cavallo
    • 1
    return OK on get
  • Laura Conti
    • 1
  1. 1.Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology CenterUniversity of TurinTurinItaly
  2. 2.Agilvax, IncAlbuquerqueUSA
  3. 3.Department of Medical Veterinary ScienceUniversity of ParmaParmaItaly

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