טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentKlechevsky Eynav
SubjectTargeting Tumor Cells and Dendritic Cells for Passive and
Active Immunotherapy of Cancer
DepartmentDepartment of Biology
Supervisor Professor Yoram Reiter
Full Thesis textFull thesis text - English Version


Abstract

 The immune system works to protect us against infectious agents and eliminate infected or cancer cells. However, when dysregulated it can also harm us, as seen in autoimmune diseases and allergies. Manipulating the immune system to increase either immunity or tolerance is the foundation of immunotherapy. The immune system consists of an innate and an adaptive limb. The adaptive immune system is composed of a humoral arm based on antibodies produced by B cells and a cellular arm composed of CD4+ and CD8+ T lymphocytes. Dendritic cells (DCs) are essential to the immune system through their ability to polarize and present antigens to lymphocytes. We have focused our studies on major histocompatibility complex (MHC) Class I restricted CD8+ T cell responses and human DCs.

We prepared TCR-like antibodies that recognize MHC Class I complexed with peptides derived from human melanoma differentiation antigens gp100 and MART-1. We studied peptide-HLA-A201 specific complexes on the surface of melanoma cells. Moreover, these antibodies coupled to a toxin can specifically kill tumor cells in vitro and slow their growth when transplanted in mice. Thus, our study paves the way for the use of these antibodies to treat human melanoma and the development of similar agents against other cancer types.

I found that the DC subset used to present the antigen had an impact on the quality of the CD8+ T cell responses. Epidermal Langerhans cells (LCs) prime high avidity cytotoxic T lymphocytes (CTLs). However dermal interstitial DCs (IntDCs) induce the generation of CD8 suppressor cells. LCs also prime CD4+ T cells into both Th1 and Th2 cells, while IntDCs prime CD4+ T cells into T follicular helper cells that help B cells to efficiently switch isotype and differentiate into plasma cells. We identified a critical role for CD8 ligation in the mechanisms leading LCs to produce high avidity CTLs. Addition of anti-CD8 antibodies to cocultures of LCs and naïve CD8+ T cells considerably inhibited T cell proliferation and induce suppressor CD8+ T cells.

To increase the generation of high avidity T cells we tested a series of monoclonal antibodies specific for DCs. Targeting an antigen to DCs through DCIR, an ITIM (immunoreceptor tyrosine-based inhibitory) motif containing lectin, resulted in enhanced cross presentation by all DC subsets.

This work covers passive and active topics of immune-based therapy and may have an impact on improving the health of patients afflicted with immune related diseases.