Lokale Kontrolle von CD4+ T Zell Effektorfunktionen in Melanomen
The skin immune system plays an important role in the development of malignant tumors. It can both inhibit and promote skin tumor growth. CD4+ T cells play an important role in the regulation of melanoma immunity and can exert potent antitumor immunity on their own. To study the role of CD4+ T cells we established a TCR-transgenic mouse strain specific for the melanocytic antigen TRP1. Adoptively transferred TRP1-specific CD4+ T cells can cause autoimmune destruction of melanocytes and regression of skin melanomas in the context of prior lymphocyte depletion and adjuvant innate immune stimulation. However melanomas relapse early. The principal goal of our project in the next funding period is to understand how melanocyte-specific CD4+ T cell functions are regulated in primary cutaneous melanomas using this experimental system. The planned work is based on the central hypothesis that the ability of CD4+ T cells to cause autoimmune destruction of melanocytes and regression of primary cutaneous melanomas can be enforced by promoting effector functions of the Th17-Th9-Th1 spectrum of phenotypes. We anticipate that TRP1-specific CD4+ T cells normally shift towards exhausted, memory and regulatory phenotypes in the tumor microenvironment which then support tumor progression and angiogenesis. In this project we will first examine the phenotypic plasticity of CD4+ T cells by restimulating them with immunogenic or tolerogenic dendritic cells in vitro and in vivo (Aim 1). We will then establish strategies involving immunostimulatory nucleic acids and RNA aptamers to locally activate innate anti-viral immune pathways and re-direct dendritic cell functions which maintain anti-tumor effector functions of CD4+ T cells (Aim 2). We will use genetic tracing techniques to follow the fate of adoptively transferred CD4+ T cells in vivo, visualize their migration towards and adhesion to dendritic cells and melanoma cells, and evaluate their heterogeneity under different conditions (Aim 3). These experiments will provide important insights how effector functions of CD4+ T cells could be harnessed for the treatment of melanoma.
Immuntherapie, Melanom, T-Zellen
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