Immunologic targeting of FOXP3 in inflammatory breast cancer cells.
The forkhead transcription factor FOXP3 is necessary for induction of regulatory T lymphocytes (Tregs) and their immunosuppressive function. We have previously demonstrated that targeting Tregs by vaccination of mice with murine FOXP3 mRNA-transfected dendritic cells (DCs) elicits FOXP3-specific T cell responses and enhances tumor immunity. It is clear that FOXP3 expression is not restricted to T-cell lineage and herein, using RT-PCR, flow cytometry, and western immunoblot we demonstrate for the first time that FOXP3 is expressed in inflammatory breast cancer (IBC) cells, SUM149 (triple negative, ErbB1-activated) and SUM190 (ErbB2-overexpressing). Importantly, FOXP3-specific T cells generated in vitro using human FOXP3 RNA-transfected DCs as stimulators efficiently lyse SUM149 cells. Interestingly, an isogenic model (rSUM149) derived from SUM149 with an enhanced anti-apoptotic phenotype was resistant to FOXP3-specific T cell mediated lysis. The MHC class I cellular processing mechanism was intact in both cell lines at the protein and transcription levels suggesting that the resistance to cytolysis by rSUM149 cells was not related to MHC class I expression or to the MHC class I antigen processing machinery in these cells. Our data suggest that FOXP3 may be an effective tumor target in IBC cells however increased anti-apoptotic signaling can lead to immune evasion.
Department of Surgery, Duke University Medical Center, Durham, NC, USA.
Smita
S
Nair
Amy J
AJ
Aldrich
Eoin
E
McDonnell
Qing
Q
Cheng
Anshu
A
Aggarwal
Pujan
P
Patel
Monique M
MM
Williams
David
D
Boczkowski
H Kim
HK
Lyerly
Michael A
MA
Morse
Gayathri R
GR
Devi
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D045744:Cell Line, Tumor; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000276:immunology* / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D010641:Phenotype; D012008:Recurrence; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D015395:Histocompatibility Antigens Class I; D044786:S-Phase Kinase-Associated Proteins; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D050760:Cyclin-Dependent Kinase Inhibitor p27