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⺠but not CD4⺠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.
Subject(s)
Breast Neoplasms/drug therapy , CD8-Positive T-Lymphocytes/drug effects , Doxorubicin/administration & dosage , Protein Kinase Inhibitors/administration & dosage , Quinazolines/administration & dosage , STAT1 Transcription Factor/metabolism , Animals , Antigens, Neoplasm/immunology , Breast Neoplasms/immunology , CD8-Positive T-Lymphocytes/immunology , Cell Movement/drug effects , Cell Movement/genetics , Cells, Cultured , Chemotaxis/drug effects , Disease Models, Animal , 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 , Rats , Receptor, ErbB-2/antagonists & inhibitors , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , STAT1 Transcription Factor/genetics , STAT1 Transcription Factor/immunologyABSTRACT
Signal transducer and activator of transcription 1 (STAT1) serves in the protection of the organism against pathogens and other harmful insults. It is implicated in innate immune response, immunosurveillance, tumor-suppression, and the response to genotoxic as well as oxidative stress. We report here that 9 of 140 examined STAT1 deficient mouse mammary tumor virus-neu (MMTV-neu) mice developed differentiated ovarian teratomas, which histologically resemble benign dermatoid cysts. Conventional karyotyping revealed diploidy without structural rearrangements of the chromosomes. STAT1 proficient MMTV-neu mice with the same genetic background (FVB/N), and STAT1 deficient C57BL/6 mice failed to develop this type of tumor. This indicates that STAT1 deficiency promotes teratoma formation and this depends on MMTV-neu expression and/or the genetic background. Since ovarian teratomas are considered to develop as a consequence of alterations in the maturation of oocytes and follicular cells, we compared the ovaries from non-tumor bearing STAT1 deficient and proficient MMTV-neu mice. No detectable alterations in the number and proportion of the different follicular developmental stages were detected, implying the absence of non-redundant functions of STAT1 in normal folliculogenesis, as well as in follicular atresia. However, strong staining for STAT1 was detectable in granulosa and theca cells. These results point to a role for STAT1 in protecting from teratoma formation in a later step of tumorigenesis, e.g. by inducing apoptosis and eliminating premature or aberrantly formed follicles which have the potential to transform into teratomas.
