Dr. Sevko, Alexandra - Postdoc, Tel. 0621-383-3770
Ramacher, Marcel - PhD student, Tel. 0621-383-3770
Flores-Guzman, Fernando - PhD student, Tel. 0621-383-3770
Stemke, Anastasia - PhD student, Tel. 0621-383-3774
Shevchenko, Ivan – PhD student, Tel. 0621-383-3774
Frank, Kathrin - Technician, Tel. 0621-383-2960

Melanoma is known for its poor response to currently used treatments like chemotherapy or radiation. Therefore, the development of new therapeutic strategies is of particular importance. Despite the high potential to stimulate anti-melanoma immune reactions, the results of clinical studies on melanoma immunotherapy are still not satisfactory. Insufficient anti-tumor reactivity could be due to the accumulation of immunosuppressive cells (like regulatory T cells, Treg, myeloid derived suppressor cells, MDSC, or immature tolerogenic dendritic cells) and soluble factors (such as TGF-beta, VEGF, IL-10, IL-6, IL-1beta, nitric oxide and reactive oxygen species) in the tumor microenvironment. We use a recently developed ret transgenic mouse melanoma model, which in contrast to transplantation models, represents a natural tumor-stoma interaction and closely resemble human melanoma regarding genetic alterations, histopathology and clinical development. After a short latency mice develop skin melanoma metastasizing to lymph nodes, lungs, and liver. Primary tumors and metastases expressed melanoma associated antigens tyrosinase, tyrosinase related protein (TRP)-1, TRP-2 and gp100. Functionally active TRP-2 specific memory T cells were accumulated in the bone marrow of tumor bearing mice and even at the preclinical stage of melanoma progression. These cells may be used for adoptive melanoma immunotherapy and could control disseminated melanoma cells in the bone marrow and lymph nodes. In addition, we observed an increased amount of different cells with immunosuppressive activity in lymphoid organs and melanoma lesions. Among them are CD4+CD25+FoxP3+ regulatory T cells (Treg), CD11b+Gr1+ myeloid derived suppressor cells (MDSC) and tolerogenic dendritic cells (DC). Despite the efficient Treg depletion from lymphoid organs of transgenic mice, melanoma development was not delayed suggesting that other immunosuppressive cells (like MDSC) could play an important role and replace immunosuppressive, tumor promoting functions of Treg. Moreover, we showed a critical role of constitutively activated p38 MAPK in the acquirement of tolerogenic pattern by DC that contributed to T-cell suppression. 

Using ret transgenic mouse melanoma model, we aim to elucidate molecular mechanisms of melanoma-induced immunosuppression and to develop an innovative strategy of human melanoma immunotherapy including adoptive transfer of tumor specific activated memory T cells and neutralization of the immunosuppressive activity MDSC, Treg and tolerogenic DC.

Veröffentlichungen "Umansky V" in Pubmed