Identification of immunosuppressive mechanisms in glioblastomas and their evaluation as therapeutic targets
Little progress has been made in treating glioblastoma patients within the last few decades and their prognosis is still dismal. To date, the most promising treatment strategies are immunotherapeutic approaches. The main goal of these therapies is to activate the immune system of the patient in such a way that a tumor-specific immune response is mounted, through which the tumor cells are selectively recognized and destroyed. A major obstacle of these immunotherapeutic approaches is, however, that glioblastomas and other tumors have developed efficient mechanism to escape T cell recognition and immune-mediated destruction.
In previous work we could show that the selection pressure exerted by the immune system leads to a clonal selection in glioblastomas in an immunocompetent mouse model that differs strikingly from the clonal composition in tumors in immunodeficient mice.
This findings raises the question whether clones that become quantitatively predominant in the immunocompetent model possess greater immunosuppressive capabilities than others. Another important question is whether identical or heterogeneous immunosuppressive mechanisms exist in the prevailing clones in wildtype mice and whether cooperative effects between different clones exist. To address these questions, the following analyses will be performed:
- Genes will be identified that are responsible for the manifestation of the immunosuppressive milieu in glioblastomas. In particular, the gene signature of the tumor cells will be distinguished from that of the host cells.
- The expression of identified immunomodulatory candidate genes will be validated on murine and human tumor tissue.
- The functional relevance of candidate genes for the interaction between tumor cells and T cells will be investigated.
- The effect of specific inhibitors for selected target molecules will be evaluated in syngeneic mouse mouse glioma models. In addition, mechanistic analyses will be performed to assess the immunological mechanism of the treatment.
Another important mechanisms of tumor-mediated immunosuppression is the secretion of extracellular tumor vesicles (tEVs). These include exosomes and microvesicles which can also be detected by "liquid biopsy" in the blood of patients and which contain important "bio-information" about the tumor of origin. Furthermore, EVs can be taken up by other cells and can change the phenotype of the recipient cell via direct receptor binding, endocytosis or fusion of the EV membrane with the recipient cell membrane and transfer of the incorporated molecules.
Glioblastoma tEVs are known to exert immunosuppressive effects on T cells and other immune cells. However, virtually nothing is known about the effects that the immune system in turn has on the tEVs. To address this question, the following analyses will be performed:
- The influence of activated T cells on the secretion and the immunosuppressive phenotype of glioma-derived tEVs will be investigated in vitro.
- The mechanism by which T cells cause "immuno-editing" of glioma tEVs will be analyzed. In particular it will be determined whether alterations of the tEV phenotype require direct contact with T cells or can also be provoked via cytokines and/or EVs secreted from T cells.
In summary, these studies will help to better understand how immunosuppressive mechanisms work in the tumor milieu and to find out at which level of intercellular communication between tumor cells and immune cells this system is amenable to therapeutic targeting.