Response of established human breast tumors to vaccination with mammaglobin-A cDNA.

Abstract

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.

• Authors: Kishore Narayanan, Andrés Jaramillo, Nicholas D Benshoff, Lacey G Campbell, Timothy P Fleming, Jill R Dietz, T Mohanakumar
• Journal: Journal of the National Cancer Institute (J Natl Cancer Inst) Vol. 96 Issue 18 Pg. 1388-96 (Sep 15 2004) ISSN: 1460-2105 [Electronic] United States
• PMID: 15367572 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cancer Vaccines
• DNA, Complementary
• Epitopes
• Mammaglobin A
• Neoplasm Proteins
• SCGB2A2 protein, human
• Uteroglobin

Topics

• Animals
• Breast Neoplasms (drug therapy, immunology)
• CD8-Positive T-Lymphocytes (immunology)
• Cancer Vaccines (pharmacology, therapeutic use)
• DNA, Complementary (therapeutic use)
• Disease Models, Animal
• Epitopes
• Female
• Humans
• Immunotherapy (methods)
• Mammaglobin A
• Mice
• Mice, Transgenic
• Neoplasm Proteins (genetics, pharmacology, therapeutic use)
• T-Lymphocytes, Cytotoxic (immunology)
• Uteroglobin (genetics, pharmacology, therapeutic use)