Mergim Meta, Natalie Fuchs
Cathepsin S (CCS) is a secreted cysteine protease that cleaves certain extracellular matrix proteins, regulates antigen presentation in antigen presenting cells (APC), and promotes M2-type macrophage and dendritic cell polarization. CCS is overexpressed in many solid cancers, and overall appears to promote an immune suppressive and tumor promoting microenvironment. While most data suggest that CCS inhibition or knock-down promotes anti-cancer immunity, cell specific inhibition, especially in myeloid cells, appears to be important for therapeutic efficacy. This makes the design of CCS selective inhibitors and their targeting to tumor associated M2-type macrophages (TAM) and DC an attractive therapeutic strategy compared to the use of non-selective immunosuppressive compounds or untargeted approaches.
In our group, we focus on the design of selective small molecule CCS inhibitors that are optimized in terms of potency, selectivity and pharmacokinetics. In cooperation with the research groups of L. Nuhn, Prof. K. Landfester, Prof. T. Weil (Max Planck Institute for Polymer Research, Mainz), Prof. T. Opatz, Prof. M. Barz (Institute of Organic Chemistry, University of Mainz) and Prof. D. Schuppan (Institute of Translational Immunology, Univ. Med. Center, Mainz), we investigate the targeting of these inhibitors to TAM using nanocarriers that are functionalized for a directed delivery.
This project is part of the Sonderforschungsbereich 1066 (SFB 1066).
Figure 1: (A) Crystal structure of CCS in complex with a covalent ligand (pdb: 1ms6). (B) Overexpression or mutation of CCS leads to an increased tumor growth and progression of follicular lymphoma (Bararia D., Hildebrand J.A., Stolz S., et al. Cathepsin S Alterations Induce a Tumor-Promoting Immune Microenvironment in Follicular Lymphoma. Cell Rep. 2020; 31(5):107522.).
Fuchs, N.; Meta, M.; Schuppan, D.; Nuhn, L.; Schirmeister, T. Novel Opportunities for Cathepsin S Inhibitors in Cancer Immunotherapy by Nanocarrier-Mediated Delivery. Cells 2020, 9, 2021.