Universität Tübingen
Aktivierung der angeborenen und adaptiven Immunantwort und deren Bedeutung bei der Immunantwort gegenüber malignen Gliomen
Abstract
The immune system is essential in guarding the body against pathogens and tumor cells. Immunity has many facets, the dichotomy separating innate and adaptive immunity in the last decades, nowadays emerges as evolutionary consecutive with interdepending pathways and continuative receptor evolution. The complexicity of the somatic rearrangement of TCR genes guarantees virtually infinite variability in the specificity of TCRs expressed on naïve T cells, i.e. costimulated via CD27/CD70 interaction, but relies on the body's rapid innate defense mechanisms where receptors with consistent PRR recognise PAMP transmitting valuable signals to the adaptive immune system, i.e. via TLR, activated by ssRNA. Thus it is not astonishing that TLR are accounted as the interface between innate and adaptive immunity (242). It actually becomes clear that the innate arm of immunity links with its adaptive counterpart in tumor immune surveillance also via NK cells, i.e. with NKG2D as a receptor of an activatory pathway. Proteomic analysis of unactivated and activated human NK cell membrane-enriched fractions demonstrated that activated NK cells can efficiently stimulate T cells, since NK cells upregulate MHC class II molecules and multiple ligands for TCR costimulatory molecules (243). Combining these findings with our improved understanding of cancer biology has helped to understand how to configure immunological strategies against the "hallmarks of cancer" (244). Encounter the escape of immune surveillance and the immunosuppressive properties of glioma cells (chapter 1), i.e. by TGF- , are the major challenges in our laboratory and were the main topics in my Ph.D. work. In my Ph.D. research I have thus explored several novel approaches aiming at engaging immune surveillance via direct activation of adaptive immunity or by more indirect ways via innate pathways and at an improved understanding of the immune-paralysing capacities of glioma cells. While the connections between these various aspects of glioma biology may not be apparent at first sight, there are good reasons for taking a combined look at the complex interactions of innate and adaptive immunity and tumor immunology. Tumor immune surveillance is mediated by immune effector cells that selectively kill cancer cells. Activated T and NK attack their targets by the expression of death ligands (245, 246) and by secretion of cytotoxic granules (87, 247) and thus seek to activate both the death receptor and the intracellular apoptotic pathway. An apoptosis-resistant target cell is therefore less susceptible to immune-mediated lysis. Sensitization of tumor cells for apoptotic stimuli could therefore enhance the efficacy of ongoing anti-tumor immune responses. Further, activation of the costimulatory pathways, e.g. using CD70 transgenes or ssRNAs may be beneficial when the tumor may strike back and induce apoptosis in tumor-infiltrating lymphocytes by various mechanisms, including the expression of CD95/FasL, HLA-G or TGF- (140, 248-250). Finally, therapeutic induction of apoptosis via these mechanisms is thought to provide a source of antigens that can be taken up and presented by professional APC, resulting in an anti-tumor immune response. The mounting of a productive anti-tumor immune response may be prevented by immune-inhibitory signals sent out by the tumor itself. Therefore, a costimulation-based reduction of large tumor masses may require the simultaneous relief of tumor-dependent immunosuppression in order to be followed by a productive immune response that can finally clear residual glioma cells dispersed in the brain.
Author and committee
dc:creator, dc:contributor.*- Author
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- Aulwurm, Steffen Alexander
Identifiers
dc:identifier.*- Identifier
- hdl:10900/48743