Response of established human breast tumors to vaccination with mammaglobin-A cDNA.
BACKGROUND
A novel breast cancer-associated antigen, mammaglobin-A, is expressed in 80% of primary breast tumors. The characterization of immune responses against this highly expressed breast cancer-specific antigen would be of value in the development of new therapeutic strategies for breast cancer.


METHODS
We developed an in vivo model using human leukocyte antigen-A*0201/human CD8+ (HLA-A2+/hCD8+) double-transgenic mice to define the epitopes and to study the level of protection acquired by mammaglobin-A cDNA vaccination toward mammaglobin-A+/HLA-A2+ breast cancer cell lines. Mammaglobin-A epitopes were identified using an HLA class I peptide binding prediction computer program, and their activity was verified using gamma interferon ELISPOT and cytotoxicity assays.


RESULTS
We identified seven mammaglobin-A-derived candidate epitopes that bind the HLA-A*0201 molecule (Mam-A2.1-7). CD8+ cytotoxic T lymphocytes (CTLs) from HLA-A2+/hCD8+ mice reacted to the Mam-A2.1 (amino acids [aa] 83-92, LIYDSSLCDL), Mam-A2.2 (aa 2-10, KLLMVLMLA), Mam-A2.4 (aa 66-74, FLNQTDETL), and Mam-A2.6 (aa 32-40, MQLIYDSSL) epitopes. CD8+ CTLs from breast cancer patients also recognized a similar epitope pattern as did those in the HLA-A2+/hCD8 mice and reacted to the Mam-A2.1, Mam-A2.2, Mam-A2.3, Mam-A2.4, and Mam-A2.7 epitopes. Passive transfer of mammaglobin-A-reactive CTLs into SCID (severe combined immunodeficient) beige mice with actively growing mammaglobin-A+ tumors resulted in statistically significant regression (P<.001) in the growth of the tumors.


CONCLUSIONS
The HLA-A2+/hCD8+ mouse represents a valuable animal model to characterize the HLA-A*0201-restricted CD8+ CTL immune response to mammaglobin-A in vivo, and the data reported here demonstrate the immunotherapeutic potential of mammaglobin-A for the treatment and/or prevention of breast cancer.
Narayanan
Kishore
K
Department of Surgery, Washington University School of Medicine, Box 8109-3328, CSRB, 660 S. Euclid Ave., St. Louis, MO, 63110, USA.
Jaramillo
Andrés
A
Benshoff
Nicholas D
ND
Campbell
Lacey G
LG
Fleming
Timothy P
TP
Dietz
Jill R
JR
Mohanakumar
T
T
D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000494:pharmacology* / Q000627:therapeutic use; D018076:DNA, Complementary / Q000627:therapeutic use; D004195:Disease Models, Animal; D000939:Epitopes; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D060785:Mammaglobin A; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014598:Uteroglobin / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use
D019496:Cancer Vaccines; D018076:DNA, Complementary; D000939:Epitopes; D060785:Mammaglobin A; D009363:Neoplasm Proteins; C556448:SCGB2A2 protein, human; D014598:Uteroglobin