Therapeutic application of T cell targets and TAM inhibitors
- Experimental Neurosurgery, Prof. Christel Herold-Mende -
Immunotherapeutic approaches are increasingly being tested in brain tumors in regard to their safety and efficacy. Some reasons are the systemic mode of action of these approaches and their ability to target tumor cells more specifically than, for example, conventional standard therapy. However, there is a growing body of evidence that anti-tumor immune responses in an immunosuppressive tumor microenvironment are often attenuated. The exact mechanisms are so far not well understood. During the first two funding periods of the Anni Hofmann Foundation, we therefore aimed to extend our knowledge on the immunological milieu in glioblastoma, especially during tumor progression and its impact on patients’ survival. In addition, we focused on the identification of suitable targets for future immunotherapies as our knowledge in this regard is also very limited, but an essential prerequisite for the successful use of such treatments. We were able to identify immunogenic tumor antigens (TAAs) by using the PF2D-IFN-ɣ-ELISpot method, which are shared by primary and recurrent tumors, and are endowed with a high tumor specificity regarding their recognition by T cells (Rapp et al., 2017; Dettling et al., 2018).
Over the last years, it has been demonstrated that tumor cells can escape immune responses directed against single TAAs. Thus, a potent vaccine should contain many broadly expressed and highly immunogenic antigens, so that even after a reduced expression of one or more antigens, the tumor control by the immune system is maintained. Accordingly, we want to expand our "warehouse" of TAAs with high tumor specificity and pronounced expression. For this purpose, we will continue to use the PF2D-IFN-ɣ ELISpot method, focusing on tumors which have a comparatively high T cell infiltration and for which an increased recognition of immunogenic tumor antigens can be assumed. Upon confirmation of the tumor-specific immunogenicity of the identified antigens in healthy donors and in independent GBM patients, the characterization of mRNA and protein expression levels in tumor and normal tissue samples will be performed in order to further assess the suitability of the identified antigens as treatment targets.
To better evaluate the heterogeneity of our TAAs and to facilitate the personalized selection of suitable TAAs for future immunotherapy, the simultaneous expression of the identified TAAs will be studied using single molecular fluorescence in situ hybridization (smFISH) analysis.
Due to the high infiltration of immunosuppressive and tumor-promoting tumor-associated microglia cells and macrophages (TAMs) in GBM tumor tissues, this immune cell population is becoming increasingly important as a target for glioblastoma therapy (Rösch et al., 2018). Different approaches including the inhibition of M2-polarized TAMs or their repolarization towards the immunogenic M1 phenotype, as well as approaches aiming to deplete or decrease differentiation of TAMs, are currently being pursued. Specific antibodies and small molecule inhibitors, which due to their small size can easily pass the blood-brain barrier and therefore may be particularly suitable for the therapy of brain tumor diseases, currently gain a lot of attention. In order to reverse the impairment of T cell responses caused by TAMs, a series of available TAM inhibitors will be evaluated. The robustness of these data will be confirmed in patient-related 3D models. Finally, these models will be used in combinatorial treatments to test whether the inhibition of anti-inflammatory TAMs leads to a better response to therapy.