ABSTRACT
Modification of vaccine carriers by decoration with glycans can enhance binding to and even targeting of dendritic cells (DCs), thus augmenting vaccine efficacy. To find a specific glycan-"vector" it is necessary to know glycan-binding profile of DCs. This task is not trivial; the small number of circulating blood DCs available for isolation hinders screening and therefore advancement of the profiling. It would be more convenient to employ long-term cell cultures or even primary DCs from murine blood. We therefore examined whether THP-1 (human monocyte cell line) and DC2.4 (immature murine DC-like cell line) could serve as a model for human DCs. These cells were probed with a set of glycans previously identified as binding to circulating human CD14low/-CD16+CD83+ DCs. In addition, we tested a subpopulation of murine CD14low/-CD80+СD11c+CD16+ cells reported as relating to the human CD14low/-CD16+CD83+ cells. Manα1-3(Manα1-6)Manß1-4GlcNAcß1-4GlcNAcß bound to both the cell lines and the murine CD14low/-CD80+СD11c+CD16+ cells. Primary cells, but not the cell cultures, were capable of binding GalNAcα1-3Galß (Adi), the most potent ligand for binding to human circulating DCs. In conclusion, not one of the studied cell lines proved an adequate model for DCs processes involving lectin binding. Although the glycan-binding profile of BYRB-Rb (8.17)1Iem mouse DCs could prove useful for assessing human DCs, important glycan interactions were missing, a situation which was aggravated when employing cells from the BALB/c strain. Accordingly, one must treat results from murine work with caution when seeking vaccine targeting of human DCs, and certainly should avoid cell lines such as THP-1 and DC2.4 cells.
Subject(s)
Dendritic Cells/metabolism , Polysaccharides/metabolism , Animals , Humans , Lectins/metabolism , Male , Mice , Mice, Inbred BALB C , Polysaccharides/chemistry , Protein Binding , THP-1 CellsABSTRACT
The development of new approaches to breast cancer (BC) early diagnosis is an important objective of modern oncology. Although the role of the immune system in cancer initiation process was experimentally well established, the prognostic value of cellular blood immunological parameters (CBIPs) for BC onset prediction was not demonstrated either in clinics or in mouse models. In this study, we focused on revealing informative CBIPs for mammary cancer (MC) onset prediction in the BLRB/BYRB mouse model with a high incidence of natural MC development. Blood samples were collected from 80 aging females of these original mouse strains, 12 basic CBIPs were estimated by flow cytometry. Then mice were followed up for 28 weeks, and the outcome of females (MC diagnosis, death without MC or MC-free survival) was registered. We estimated the patterns of changes in CBIPs with age and in accordance with the outcome. An increasing imbalance in 11 CBIPs during natural aging of females clearly resembled human immunosenescence phenomenon and several patterns corresponded to the results obtained on cancer-free members of BC-affected families. We stratified heterogeneous female population into middle-aged and old subgroups. Low NK-cell levels in middle-aged mice and low B-cell along with high T-helper levels in old mice distinguished females with developed MC from the other groups. We found a reliable correlation of several CBIPs with age at MC diagnosis and survival of cancer-bearing females. Thus, we demonstrated the predictive potential of CBIPs as a basis for the development of prognostic models for BC onset in clinics.
Subject(s)
Aging/immunology , B-Lymphocytes/immunology , Breast Neoplasms/diagnosis , Killer Cells, Natural/immunology , T-Lymphocytes, Helper-Inducer/immunology , Animals , Blood Circulation , Breast Neoplasms/immunology , Disease Models, Animal , Early Detection of Cancer , Female , Humans , Mice , Mice, Mutant Strains , Predictive Value of Tests , PrognosisABSTRACT
Earlier, naturally arising mammary cancer in BLRB female mice was shown to reproduce some key pathological characteristics of the familial set of human breast cancer. Then we advanced a novel 3S-paradigm of anticancer research that helped to develop selection criteria and to estimate benefit/risk of local interleukin-2 (IL-2) effects in this spontaneous mouse model. In this paper, the efficacy of single and triple local IL-2 doses is compared using properly selected murine BLRB females based on our previously published data. Only BLRB females bearing spontaneous mammary tumors without subclinical period were used. The tumor growth rate and recipient survival of single and triple IL-2 applications were compared with corresponding parameter values of untreated control. Tumor growth rate was decreased in both experimental groups versus control parameter values. Single IL-2 application resulted in a significant prolongation of the average survival time while triple application caused acute tumor rejection in some females decreasing the survival time of the rest of the recipients. As a result, proper treatment protocol in accurately selected females allowed increasing the complete response rate to 14% in spontaneous mouse model of breast cancer. In conclusion, our approaches may demonstrate the principle methodology developing preselection procedure for breast cancer patients for local IL-2 therapy application.
