Phenotypic Therapy and Immune Escape in Cancer

Project 7Unraveling the phenotypic coevolution of melanoma cells and neutrophils fostering metastasis and therapy resistance

‚ÄčProject 7 1
Tumor-associated neutrophil granulocytes (TAN) constitute a significant part of the immunological infiltrate in solid tumors. Developing melanomas recruit migrating TAN into the vicinity or even the very center of the tumor. TAN are equipped with an enormous functional heterogeneity. On the one hand they can foster tumor growth, dissemination and the development of therapy-resistance. On the other hand, clearly anti-tumorigenic TAN have been described. However, the molecular mechanisms behind this diverse functionality are not understood. Hence it remains impossible to modulate TANs for the improvement of tumor therapy. Here we will investigate TAN during the development of metastasizing melanoma thereby making use of unique experimental systems as well as primary patient material. We have developed innovative mouse models with transplanted or spontaneously developing melanomas that at the same time carry genetically fluorescent TAN for direct microscopic visualization. We will investigate how TANs modulate the efficacy of therapeutic immune checkpoint blockade. To achieve this, PhD candidates will directly visualize TAN using intravital 2-photon microscopy and then perform a comprehensive molecular characterization of the cells after isolation. By comparing TANs with peripheral neutrophils of the same host or controls students will investigate features of pro- and anti-tumorigenic TANs. Then they will test, whether failed immunotherapy can be re-activated by depletion or access-inhibition of TANs. In addition, students will investigate, whether autonomous migration of neutrophils is changed in tumor-bearing animals and patients. They will also study, whether changes in neutrophil migration allow a prognosis on the efficacy of immune checkpoint blockers for human melanoma. At the end we aim at a new understanding on the function of TAN which might then allow to infer novel treatment options for metastasizing human tumors via targeted modulation of TAN function.

 

Contact

PD Dr. rer. nat. Iris Helfrich
Department of Dermatology
German Cancer Consortium (DKTK)
University Hospital Essen

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Prof. Dr. rer. nat. Matthias Gunzer
Institute of Experimental Immunology & Imaging
Medical Faculty
University of Duisburg-Essen

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