Mechanistic study on the functional and prognostic role of eosinophils in targeted therapy of malignant melanoma.

• Applicant: Professor Dr. Bastian Schilling
• Subject Area: Dermatology ; Immunology
• Term: from 2016 to 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 320830175

Malignant melanoma is the deadliest form of skin cancer. The recent discovery of recurrent mutations in BRAF, which support tumor cell proliferation and survival, has led to the development of new targeted therapeutics. These targetd therapies can achieve tumor regression in the majority of patients with tumors harboring a mutated BRAFV600, thereby improving survival of patients with advanced melanoma. However, tumors eventually become resistant and progress. To overcome this, efficacy of targeted agents might be enhanced by combinations with immunotherapies, which can induce durable tumor regression. To conduct such combinatorial treatments, the immunological aspects of targeted therapies need to be explored for synergistic effects but also for adverse reactions. In preliminary studies, we could show that patients with a high peripheral eosinophil count benefit from selective BRAF-inhibitors more profoundly than those with low counts. Eosinophils are myeloid cells that seem to play a major role in the development of allergies but also in fighting infections by parasites. Their role in anti-tumor immunity is largely elusive. In in vitro experiments, we were able to show that treatment of melanoma cells with a selective BRAF-inhibitor enhances killing of tumor cells by eosinophils significantly. In contrast, we found preliminary evidence that neutrophils support melanoma cell survival. Based on these preliminary data, we now want to further characterize the interaction of eosinophils and neutrophils with melanoma cells functionally and molecular. In addition, the mode of action of selective BRAF-inhibitors on this interaction will be investigated. If synergistic effects can be observed, therapeutics directing eosinophils into metastases might be a rationale compound in combinational therapies with targeted therapeutics. Therefore, this project wants to answer a question clinically relevant for the future therapy of melanoma. Also, it addresses fundamental aspects of the biology and the anti-tumor immunity by exerted eosinophils.

• DFG Programme: Research Grants