Lapatinib and doxorubicin enhance the Stat1-dependent antitumor immune response

Eur J Immunol. 2013 Oct;43(10):2718-29. doi: 10.1002/eji.201242505. Epub 2013 Jul 11.


The dual erbB1/2 tyrosine kinase inhibitor lapatinib as well as the anthracycline doxorubicin are both used in the therapy of HER2-positive breast cancer. Using MMTV-neu mice as an animal model for HER2-positive breast cancer, we observed enhanced tumor infiltration by IFN-γ-secreting T cells after treatment with doxorubicin and/or lapatinib. Antibody depletion experiments revealed a contribution of CD8⁺ but not CD4⁺ T cells to the antitumor effect of these drugs. Doxorubicin treatment additionally decreased the content of immunosuppressive tumor-associated macrophages (TAMs) in the tumor bed. In contrast, Stat1-deficient mice were resistant to tumor growth inhibition by lapatinib and/or doxorubicin and exhibited impaired T-cell activation and reduced T-cell infiltration of the tumor in response to drug treatment. Furthermore, Stat1-deficiency resulted in reduced expression of the T-cell chemotactic factors CXCL9, CXCL10, and CXCL11 in the tumor epithelium. The inhibition of TAM infiltration of the tumor by doxorubicin and the immunosuppressive function of TAMs were found to be Stat1 independent. Taken together, the results point to an important contribution toward enhancing T-cell and IFN-γ-based immunity by lapatinib as well as doxorubicin and emphasize the role of Stat1 in building an effective antitumor immune response.

Keywords: Antitumor immunity; CD8+ T cells; Doxorubicin; Lapatinib; Stat1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / immunology
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Movement / drug effects
  • Cell Movement / genetics
  • Cells, Cultured
  • Chemotaxis / drug effects
  • Disease Models, Animal
  • Doxorubicin / administration & dosage*
  • ErbB Receptors / antagonists & inhibitors
  • Female
  • Humans
  • In Vitro Techniques
  • Interferon-gamma / metabolism
  • Lapatinib
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Protein Kinase Inhibitors / administration & dosage*
  • Quinazolines / administration & dosage*
  • Rats
  • Receptor, ErbB-2 / antagonists & inhibitors
  • Receptor, ErbB-2 / genetics
  • Receptor, ErbB-2 / metabolism
  • STAT1 Transcription Factor / genetics
  • STAT1 Transcription Factor / immunology
  • STAT1 Transcription Factor / metabolism*


  • Antigens, Neoplasm
  • Protein Kinase Inhibitors
  • Quinazolines
  • STAT1 Transcription Factor
  • Lapatinib
  • Doxorubicin
  • Interferon-gamma
  • ErbB Receptors
  • Receptor, ErbB-2