The aim of this thesis is to generate new insights into the immunogenicity of the anaplastic lymphoma kinase (ALK) by the first comprehensive investigation of ALK-specific CD4 T cell responses. ALK fusion proteins, resulting from chromosomal translocations, are the main oncogenic drivers in anaplastic large cell lymphoma (ALCL). The aberrant ALK expression in lymphoma cells is recognized by the immune system which is reflected by spontaneous ALK- specific humoral- and T cell responses. These spontaneous immune responses can be potentially promoted by immunotherapy to mediate tumor control and long-term protection. Previous efforts to dissect mechanisms of anti-ALK immunity have primarily focused on CD8 T cells and B cells. The presence and participation of CD4 T cells in the anti-ALK immune response remains poorly characterized.The first aim of this study was the detection of ALK-specific CD4 T cells in humans. To address this, a combination of a peptide-based immunological approach with IFN-gamma ELISPOT was used to analyze peripheral blood of uniformly treated ALK+ALCL patients in clinical remission and healthy individuals for the presence of ALK-reactive CD4 T cells. In the next step, ALK-reactive CD4 T cell responses were dissected via single peptide screening to identify MHC class II restricted immunogenic ALK peptides in individual patients. The findings were integrated into immunization studies in mice to investigate ALK vaccine induced CD4 T cell responses in vivo and to explore the therapeutic efficacy of a selected ALK peptide vaccine in a syngeneic ALK- positive lymphoma model.This study provides evidence for the presence of ALK-reactive CD4 T cell responses in human and mice and led to the identification of previously undescribed CD4 T cell epitopes within the ALK protein. Furthermore, the potential and efficacy of CD4-directed ALK peptide vaccines in inducing spontaneous and therapeutically relevant ALK-specific CD4 T cell responses were demonstrated.These findings extent the knowledge on ALK immunity and provide essential information on ALK-reactive CD4 T cells, which can be potentially translated into the development of future immunotherapeutic strategies for the treatment of ALK-positive ALCL.
Verknüpfung zu Publikationen oder weiteren Datensätzen
