Use and specificity of breast cancer antigen/milk protein BA46 for generating anti-self-cytotoxic T lymphocytes by recombinant adeno-associated virus-based gene loading of dendritic cells.
Antigen-targeted immunotherapy is an emerging treatment for breast cancer. However, useful breast cancer antigens are only found in a subset of cancer patients. BA46, also known as lactadherin, is a membrane-associated glycoprotein that is expressed in most breast cancer cells but not in general hematopoietic cell populations. Moreover, it is much more difficult to generate CTLs against self-antigens. We wished to determine if the use of recombinant adeno-associated virus (rAAV) type 2 vectors for gene-loading of dendritic cells (DCs) could generate rapid, effective cytotoxic T lymphocytes (CTLs) against BA46. We were able to demonstrate that AAV/BA46/Neo-loading of DCs resulted in: (1) BA46 expression in DCs, (2) chromosomal integration of the AAV/BA46/Neo vector within DCs, (3) strong, rapid BA46-specific, MHC class I-restricted CTLs in only 1 week, (4) T-cell populations with significant interferon-gamma (IFN-gamma) expression but low IL-4 expression, (5) high CD80 and CD86 expression in DCs, and (6) high CD8:CD4 and CD8:CD56 T cell ratios. These data suggest that rAAV-loading of DCs may be useful for immunotherapeutic protocols against self-antigens in addition to viral antigens and that the BA46 antigen is potentially appropriate for cell-mediated immunotherapeutic protocols addressing ductal breast cancer.
Liu
Yong
Y
Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, Arkansas 72205, USA.
Chiriva-Internati
Maurizio
M
You
Changxuan
C
Luo
Rongcheng
R
You
Hong
H
Prasad
C Krishna
CK
Grizzi
Fabio
F
Cobos
Everardo
E
Klimberg
V Suzanne
VS
Kay
Helen
H
Mehta
Jawahar L
JL
Hermonat
Paul L
PL
D000906:Antibodies / Q000378:metabolism; D000954:Antigens, Surface / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015139:Blotting, Southern; D001943:Breast Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D045744:Cell Line, Tumor; D017931:DNA Primers; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D000229:Dependovirus / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008894:Milk Proteins / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D000906:Antibodies; D000954:Antigens, Surface; D017931:DNA Primers; C098942:MFGE8 protein, human; D008894:Milk Proteins; D015847:Interleukin-4; D007371:Interferon-gamma