Use and specificity of breast cancer antigen|[sol]|milk protein BA46 for generating anti-self-cytotoxic T lymphocytes by recombinant adeno-associated virus-based gene loading of dendritic cells

doi:doi:10.1038/sj.cgt.7700785

Cancer Gene Therapy (2005) 12, 304–312. doi:10.1038/sj.cgt.7700785 Published online 26 November 2004

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

Yong Liu¹, Maurizio Chiriva-Internati², Changxuan You³, Rongcheng Luo³, Hong You⁴, C Krishna Prasad⁴, Fabio Grizzi⁵, Everardo Cobos², V Suzanne Klimberg⁴, Helen Kay⁴, Jawahar L Mehta⁴ and Paul L Hermonat^1,4

¹Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, Arkansas 72205, USA
²Department of Microbiology and Immunology, Texas Tech University, Lubbock, Texas 79430, USA
³Department of Oncology, Nanfang Hospital, Guangzhou, Guangdong, China
⁴Department of Obstetrics and Gynecology, Slot 518, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, Arkansas 72205, USA
⁵Scientific Direction, Instituto Clinico Humanitas, Rozzano, Milano, Italy

Correspondence: Dr Paul L Hermonat, Department of Obstetrics and Gynecology, Slot 518, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, Arkansas 72205, USA. E-mail: plhermonat@uams.edu

Received 15 November 2003; Published online 26 November 2004.

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Abstract

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- (IFN-) 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.