Liu Yong, Chiriva-Internati Maurizio, You Changxuan, Luo Rongcheng, You Hong, Prasad C Krishna, Grizzi Fabio, Cobos Everardo, Klimberg V Suzanne, Kay Helen, Mehta Jawahar L, Hermonat Paul L
Department of Internal Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St., Little Rock, Arkansas 72205, USA.
Cancer Gene Ther. 2005 Mar;12(3):304-12. doi: 10.1038/sj.cgt.7700785.
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.
抗原靶向免疫疗法是一种新兴的乳腺癌治疗方法。然而，有用的乳腺癌抗原仅在一部分癌症患者中发现。BA46，也称为乳黏附素，是一种膜相关糖蛋白，在大多数乳腺癌细胞中表达，但在一般造血细胞群体中不表达。此外，针对自身抗原产生细胞毒性T淋巴细胞（CTL）要困难得多。我们希望确定使用2型重组腺相关病毒（rAAV）载体对树突状细胞（DC）进行基因加载是否能快速、有效地产生针对BA46的CTL。我们能够证明，DC的AAV/BA46/Neo加载导致：（1）DC中BA46表达；（2）AAV/BA46/Neo载体在DC内的染色体整合；（3）仅在1周内就产生强大、快速的BA46特异性、MHC I类限制性CTL；（4）T细胞群体中干扰素-γ（IFN-γ）表达显著但白细胞介素-4表达低；（5）DC中CD80和CD86表达高；（6）CD8:CD4和CD8:CD56 T细胞比率高。这些数据表明，除了病毒抗原外，DC的rAAV加载可能对针对自身抗原的免疫治疗方案有用，并且BA46抗原可能适用于针对导管乳腺癌的细胞介导免疫治疗方案。
