Abstract
Mammaglobin A (MGBA) is a novel breast cancer-associated antigen almost exclusively over-expressed in primary and metastatic human breast cancers, making it a potential therapeutic target for breast cancer. The development of dendritic cell (DC)-induced tumor antigen specific CD8+ cytotoxic T lymphocytes (CTLs) may hold promise in cancer immunotherapy. In this study we constructed recombinant replication-defective adenoviral (Ad) vectors encoding MGBA and evaluated their ability to trigger anti-tumor immunity in vitro. DCs were isolated from the human peripheral blood monocyte cells (PBMCs) of two HLA-A33+ healthy female volunteers, and infected with adenovirus carrying MGBA cDNA (Ad-MGBA). After that, the Ad-MGBA-infected DCs were used to stimulate CD8+ CTLs in vitro and the latter was used for co-culture with breast cancer cell lines. The data revealed that infection with Ad-MGBA improved DC maturation and up-regulated the expression of co-stimulatory molecules and the secretion of interleukin-12 (IL-12), but down-regulated interleukin-10 (IL-10) secretion from DCs. Ad-MGBA-infected DC-stimulated CD8+CTLs displayed the highest cytotoxicity towards HLA-A33+/MGBA+ breast cancer MDA-MB-415 cells compared with other CD8+CTL populations, and compared with the cytotoxicity towards HLA-A33−/MGBA+ breast cancer HBL-100 cells and HLA-A33−/MGBA− breast cancer MDA-MB 231 cells. In addition, Ad-MGBA-infected DC-stimulated CD8+ CTLs showed a high level of IFNγ secretion when stimulated with HLA-A33+/MGBA+ breast cancer MDA-MB-415 cells, but not when stimulated with HLA-A33−/MGBA+ HBL-100 and HLA-A33−/MGBA−MDA-MB-231 cells. In addition, killing of CD8+CTLs against breast cancer was in a major histocompability complex (MHC)-limited pattern. Finally, the data also determined the importance of TNF-α in activating DCs and T cells. These data together suggest that MGBA recombinant adenovirus-infected DCs could induce specific anti-tumor immunity against MGBA+ breast cancers, which could provide a novel strategy in the immunotherapy of breast cancer.
Highlights
Breast cancer is the most common malignancy affecting women in the world
Expression of Mammaglobin A (MGBA) Protein in Breast Cancer Cell Lines In this study, we first assessed expression of MGBA protein in these three breast cancer cell lines and found that MGBA protein was detected in MDA-MB-415 and HBL-100, but not in MDAMB-231 cells (Fig. 1)
The data showed that dendritic cell (DC) in 2 day culture expressed low levels of CD80, CD83, CD86, and HLA-DR; DCs on day 5 and 7 expressed modest levels of these proteins, while other DCs on day 7, including 7d-adenovirus carrying MGBA cDNA (Ad-MGBA) DCs, 7d-TNF-a DCs, 7d-MGBAp-TNF-a DCs, 7d-Ad-null-TNF-a DCs and 7d-Ad-MGBA-TNF-a DCs displayed high levels of these proteins (Fig. 2)
Summary
The worldwide incidence of breast cancer has significantly increased within the past several decades, and in some parts of China, it is ranked to be the most common female invasive cancer [1]. Survival rates of breast cancer patients vary greatly depending on cancer type, clinical stage, and treatment. Surgery, chemotherapy, and radiotherapy are the major options to treat breast cancer patients, but breast cancer is able to recur. The exploration of more effective and safer therapeutic modalities is urgently needed. One of these modalities is cancer immunotherapy, which is a growing field of research that studies the body’s immune system in relation to treatment of human cancers
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