Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer

Cancer Res. 2016 Jan 1;76(1):62-72. doi: 10.1158/0008-5472.CAN-15-1208. Epub 2015 Nov 13.


Resistance to therapy and lack of curative treatments for metastatic breast cancer suggest that current therapies may be missing the subpopulation of chemoresistant and radioresistant cancer stem cells (CSC). The ultimate success of any treatment may well rest on CSC eradication, but specific anti-CSC therapies are still limited. A comparison of the transcriptional profiles of murine Her2(+) breast tumor TUBO cells and their derived CSC-enriched tumorspheres has identified xCT, the functional subunit of the cystine/glutamate antiporter system xc(-), as a surface protein that is upregulated specifically in tumorspheres. We validated this finding by cytofluorimetric analysis and immunofluorescence in TUBO-derived tumorspheres and in a panel of mouse and human triple negative breast cancer cell-derived tumorspheres. We further show that downregulation of xCT impaired tumorsphere generation and altered CSC intracellular redox balance in vitro, suggesting that xCT plays a functional role in CSC biology. DNA vaccination based immunotargeting of xCT in mice challenged with syngeneic tumorsphere-derived cells delayed established subcutaneous tumor growth and strongly impaired pulmonary metastasis formation by generating anti-xCT antibodies able to alter CSC self-renewal and redox balance. Finally, anti-xCT vaccination increased CSC chemosensitivity to doxorubicin in vivo, indicating that xCT immunotargeting may be an effective adjuvant to chemotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Transport Systems / immunology*
  • Amino Acid Transport Systems / metabolism
  • Animals
  • Antigens, Neoplasm / immunology*
  • Breast Neoplasms / immunology*
  • Breast Neoplasms / pathology
  • Breast Neoplasms / therapy*
  • Cancer Vaccines / immunology
  • Cancer Vaccines / pharmacology*
  • Cell Line, Tumor
  • Cystine / immunology
  • Cystine / metabolism
  • Disease Progression
  • Female
  • Glutamic Acid / immunology
  • Glutamic Acid / metabolism
  • Humans
  • Lung Neoplasms / immunology
  • Lung Neoplasms / secondary
  • Lung Neoplasms / therapy
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • NIH 3T3 Cells
  • Neoplastic Stem Cells / immunology*
  • Neoplastic Stem Cells / pathology
  • Up-Regulation
  • Vaccines, DNA / immunology
  • Vaccines, DNA / pharmacology*
  • Xenograft Model Antitumor Assays


  • Amino Acid Transport Systems
  • Antigens, Neoplasm
  • Cancer Vaccines
  • Vaccines, DNA
  • Glutamic Acid
  • Cystine