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Induktion spontaner T-Zell-Antworten gegen Brustkrebsantigene während der Schwangerschaft und Stillzeit

Krause, Anna-Lena

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Abstract

Compared to childless (nulliparous) women, the breast cancer risk of mothers can be 50% lower. The cause of the protective effect of parity is not yet clarified. However, it has been shown that immune cells of mothers show an enhanced cytotoxicity against tumor cells. Hence, it was assumed that T cells mediate the anti-cancer effect via the recognition of tumor-associated antigens (TAA). Moreo-ver, regulatory T cells (Treg), being essential for the prevention of pathological immune responses, can also suppress anti-tumor immunity. In breast cancer patients, the intratumoral accumulation of Treg cells is associated with a lower overall survival and an increased risk of relapse. Previous studies have revealed the presence of TAA-specific T cells in the blood of breast cancer patients. On the downside, the anti-tumor immunity of these patients is frequently suppressed by TAA-specific Treg cells. The aim of this study was to investigate the induction and characteristics of spontaneous T cell re-sponses against TAA during pregnancy, which may form a lifelong immune protection against breast cancer. Furthermore, we asked whether previous pregnancies may also have an impact on the anti-tumor immunity of breast cancer patients. We isolated peripheral blood T cells from nulliparous and primigravid women, mothers and breast cancer patients and analyzed their TAA specificity, functional properties and phenotype. IFN-γ ELISpot analyses with long synthetic peptides were performed to detect the frequency of TAA specif-ic T cells in blood samples. The impact of TAA-specific Treg cells on anti-tumor immunity was as-sessed by performing the IFN-γ ELISpot analyses before and after depletion of CD4+CD25+ T cells. By applying the Treg-specificity assay, we analyzed the antigenic specificities of these Treg cells. The results of this study indicate a spontaneous induction of anti-tumor immune responses during the first trimester of pregnancy. Highly functional TAA-specific memory T cells were detected in 85% of healthy mothers, but in none of the nulliparous controls. Furthermore, we found that a lifelong immunological memory is formed, that positively impacts on anti-tumor immunity, since TAA-specific T cell responses in mothers with breast cancer were significantly stronger and less impaired by Treg cells, as compared to nullipara. The findings obtained in this thesis support the implementation of a prospective study, which corre-lates the prevalence of TAA-specific T cells with the incidence of breast cancer. Based on this study, the potential benefit of a preventive vaccine is to be estimated, which may be applied to nulliparous women.

Item Type: Dissertation
Supervisor: Beckhove, Prof. Dr. Philipp
Date of thesis defense: 22 May 2015
Date Deposited: 09 Jul 2015 05:56
Date: 2015
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Service facilities > German Cancer Research Center (DKFZ)
Subjects: 500 Natural sciences and mathematics
570 Life sciences
Controlled Keywords: Brustkrebs, T-Lymphozyt, Tumorantigen, Schwangerschaft, Impfstoff, Krebsrisiko
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