Project Details
Projekt
Unraveling the plasticity and tumor-promoting role of neutrophils as a function of tumor heterogeneity
Subject Area
Dermatology
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 405344257
Tumor-associated neutrophil granulocytes (TAN) form an essential component of the immunological infiltrate of solid tumors, such as melanoma. Taking advantage of their ability to actively migrate, TAN are recruited to the vicinity and center of melanomas. It has been shown that these cells exhibit enormous functional heterogeneity. On the one hand, they can contribute to increased tumor growth, more aggressive metastasis and development of resistance to tumor therapies through a number of mechanisms. On the other hand, TANs have also been described that exert significant tumor control. Due to the lack of suitable preclinical models to date, the underlying mechanisms of this different functionality (pro- versus anti-tumor) are not well elucidated. Thus, it is not yet possible to selectively influence TAN to improve the response to targeted tumor therapy. In this project, TAN will be investigated in the context of metastatic melanoma using newly generated experimental systems and primary patient material. For this purpose, innovative mouse models with transplanted or spontaneously developing melanomas are used, in which the TAN are simultaneously genetically labeled to make them visible. The transplanted tumors show a defined plasticity in terms of sensitivity to therapies. This plasticity is also reflected in the spontaneously developing models. In the first funding phase, we were able to show that there are melanomas that are resistant to immune checkpoint blockers but are strongly slowed down in growth by removal of TAN. We initially clarified the functional and molecular identity of TAN using complex proteomics. With the help of intravital microscopy directly inside the tumor, we were able to analyze the interaction of TAN and tumors and gain initial information in an in vitro screen on how the migration of TAN into the tumors is controlled. In the second funding phase, we now want to clarify the molecular characteristics of TAN in detail, not only in melanoma, but also in other tumor entities of the FOR. Furthermore, we want to understand how TAN support tumors in escaping from immunotherapies and which clinically applicable inhibitors exist that can prevent the migration of TAN into tumors. In addition, one goal is to use barcoding to find out which tumor cell characteristics develop in immunotherapy-resistant and TAN-independent persister cells. The aim is, on the one hand, to identify possible new therapeutic concepts that target the modulation of TAN and, on the other hand, to define new TAN-related biomarkers that will allow prediction of the effectiveness of a therapy in the future. Furthermore, within the framework of PhenoTImE, the validity of the insights gained for other tumor entities is to be clarified.
DFG Programme
Clinical Research Units
