title: Lapatinib and doxorubicin enhance the Stat1-dependent antitumor immune response.
abstract: 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.
authors.affiliation: Division of Medical Biochemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria.
authors.forename: Lára
authors.initials: L
authors.lastname: Hannesdóttir
authors.forename: Piotr
authors.initials: P
authors.lastname: Tymoszuk
authors.forename: Nirmala
authors.initials: N
authors.lastname: Parajuli
authors.forename: Marie-Helene
authors.initials: MH
authors.lastname: Wasmer
authors.forename: Sonja
authors.initials: S
authors.lastname: Philipp
authors.forename: Nina
authors.initials: N
authors.lastname: Daschil
authors.forename: Sebak
authors.initials: S
authors.lastname: Datta
authors.forename: Johann-Benedikt
authors.initials: JB
authors.lastname: Koller
authors.forename: Christoph H
authors.initials: CH
authors.lastname: Tripp
authors.forename: Patrizia
authors.initials: P
authors.lastname: Stoitzner
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Müller-Holzner
authors.forename: Gerrit Jan
authors.initials: GJ
authors.lastname: Wiegers
authors.forename: Veronika
authors.initials: V
authors.lastname: Sexl
authors.forename: Andreas
authors.initials: A
authors.lastname: Villunger
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Doppler
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000378:metabolism; D000077341:Lapatinib; D008213:Lymphocyte Activation / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011799:Quinazolines / Q000008:administration & dosage*; D051381:Rats; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D004317:Doxorubicin; D066246:ErbB Receptors; D007371:Interferon-gamma; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D050794:STAT1 Transcription Factor
keywords: Antitumor immunity; CD8+ T cells; Doxorubicin; Lapatinib; Stat1