Medical University of Vienna
Laboratory of Molecular Dermato-Oncology and Tumor Immunology (Head)
Department of Dermatology
Waehringer Guertel 18-20
1090 Vienna, Austria
Phone: +43 1 40400-77020
Fax: +43 1 40160-76990
Human melanoma is a heterogeneous disease at the genetic as well as the cellular level. Both genetic switches and changes in the cellular composition and activity of the different cell types within the tumor (the tumor microenvironment) critically control tumor growth, progression and therapy responses. B cells are capable to profoundly stimulate or dampen immune responses and are a substantial part of the melanoma microenvironment. Their functional role in human melanoma, however, is still unknown. We aim to understand their communication with tumor cells as well as their cross-talk to other cell types within the tumor microenvironment to identify novel paths to immunotherapy of human melanoma.
Characterization of tumor-promoting and -protective human melanoma B cell subsets. The tumor microenvironment (TME) critically controls anticancer T cell responses1. Complementary protein and RNA data from our lab indicate that the number of B cells in the TME of primary melanomas robustly correlate with a better overall survival of patients2. Paradoxically, we could recently show that an increase of B cell numbers can promote resistance of human melanoma cells to kinase inhibitors via IGF1 and FGFR3 signaling3. We hypothesize that exposure to kinase inhibitors may induce a tumor-promoting phenotype in human B cells. In this project B cells will be isolated from human pre-therapy melanoma tumors, exposed or not to kinase inhibitors, phenotyped, subjected to genomic, ((sc)RNAseq)/(phospho)proteomic profiling and compared for direct and indirect modulation of T cell activity against model antigens in organoid 3D skin reconstructs with autologous T cells and Mɸ. Importantly, we have refined protocols to obtain transcript and proteome profiles from only 250-500 cells4. We expect to identify functionally-annotated molecular profiles that are associated with a tumor-protective or -promoting B cell phenotype. The respective molecular profiles will help us to identify candidate signaling structures and/or hubs for in vitro interference studies with T cell activity in 3D co-cultures above. These results will differentiate the molecular mechanisms of B cell mediated tumor-protective and -promoting effects and identify novel and more specific targets for therapy. All experiments are performed with cells from an unmodified source, i.e. patient-derived tumor and PBMC samples. (Collaborations: Egger-epigenetics; Eferl-evaluation of metabolic signatures; Brostjan- co-cultures with Mɸ).
- Somasundaram, R.; Herlyn, M.; Wagner, S. N. The Role of Tumor Microenvironment in Melanoma Therapy Resistance. Melanoma Manag. 2016, 3 (1), 23–32. doi.org/10.2217/mmt.15.37.
- Garg, K.; Maurer, M.; Griss, J.; Brüggen, M.-C.; Wolf, I. H.; Wagner, C.; Willi, N.; Mertz, K. D.; Wagner, S. N. Tumor-Associated B Cells in Cutaneous Primary Melanoma and Improved Clinical Outcome. Hum. Pathol. 2016, 54, 157–164. doi.org/10.1016/j.humpath.2016.03.022.
- Somasundaram, R.; Zhang, G.; Fukunaga-Kalabis, M.; Perego, M.; Krepler, C.; Xu, X.; Wagner, C.; Hristova, D.; Zhang, J.; Tian, T.; et al. Tumor-Associated B-Cells Induce Tumor Heterogeneity and Therapy Resistance. Nat. Commun. 2017, 8 (1), 607. doi.org/10.1038/s41467-017-00452-4.
- Maurer, M.; Müller, A. C.; Parapatics, K.; Pickl, W. F.; Wagner, C.; Rudashevskaya, E. L.; Breitwieser, F. P.; Colinge, J.; Garg, K.; Griss, J.; et al. Comprehensive Comparative and Semiquantitative Proteome of a Very Low Number of Native and Matched Epstein-Barr-Virus-Transformed B Lymphocytes Infiltrating Human Melanoma. J. Proteome Res. 2014, 13 (6), 2830–2845. doi.org/10.1021/pr401270y.