Fibroblast activation protein (FAP), also known as seprase, is a post-prolyl proteolytic enzyme with both endopeptidase and dipeptidyl peptidase activity. FAP is typically highly expressed in 90% of all epithelial tumors, whereas it’s expression is low to undetectable in most normal adult tissues.1
Recently, it has been suggested that FAP plays an important role in the induction of immunosuppression in the tumor microenvironment.2, 3 Moreover, it has been suggested that FAP+ cancer-associated fibroblasts (FAP+CAFs) are responsible for resistance to immune checkpoint inhibitors (anti-PD1 and anti-CTLA4 immunotherapy). 3 Given the results, FAP can be a very interesting predictive biomarker for immunotherapy resistance. Nevertheless, the exact function of FAP in immunosuppression remains largely unknown.
Currently, our research focusses on the development and validation of different tools (e.g. nanobodies, activity assays, activity-based probes) to study FAP as a predictive biomarker in different matrices (blood, urine, histological sections of tumors,…). These tools can be exploited to investigate the applicability of FAP as a predictive biomarker in immunotherapy resistance.
Secondly, we aim to unravel the function of FAP’s proteolytic activity in the tumor microenvironment. Hence, we try to search for new natural cancer-related FAP substrates in a cell-culture environment.
Researchers of the laboratory of Medical Biochemistry contributed to earlier research on fibroblast activation protein. Recently, our research group developed and validated a new FAP activity assay that can measure FAP’s activity in plasma samples, with selectivity towards the related serine proteases, including prolyl oligopeptidase (PREP).4 Moreover, an in-situ assay was developed to detect in situ FAP activity in FAP-expressing cells. 5 Our group is also specialized in testing newly synthetized compounds against FAP for their affinity and selectivity.
Literature
- [1] Brennen, W. N., Isaacs, J. T., and Denmeade, S. R. (2012) Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy, Molecular cancer therapeutics 11, 257-266.
- [2] Chen, L., Qiu, X., Wang, X., and He, J. (2017) FAP positive fibroblasts induce immune checkpoint blockade resistance in colorectal cancer via promoting immunosuppression, Biochemical and biophysical research communications 487, 8-14.
- [3] Feig, C., Jones, J. O., Kraman, M., Wells, R. J., Deonarine, A., Chan, D. S., Connell, C. M., Roberts, E. W., Zhao, Q., Caballero, O. L., Teichmann, S. A., Janowitz, T., Jodrell, D. I., Tuveson, D. A., and Fearon, D. T. (2013) Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer, Proceedings of the National Academy of Sciences of the United States of America 110, 20212-20217.
- [4] Bracke, A., Van Elzen, R., Van Der Veken, P., Augustyns, K., De Meester, I., and Lambeir, A. M. (2019) The development and validation of a combined kinetic fluorometric activity assay for fibroblast activation protein alpha and prolyl oligopeptidase in plasma, Clinica chimica acta; international journal of clinical chemistry 495, 154-160.
- [5] De Decker, A., Vliegen, G., Van Rompaey, D., Peeraer, A., Bracke, A., Verckist, L., Jansen, K., Geiss-Friedlander, R., Augustyns, K., De Winter, H., De Meester, I., Lambeir, A. M., and Van der Veken, P. (2019) Novel Small Molecule-Derived, Highly Selective Substrates for Fibroblast Activation Protein (FAP), ACS medicinal chemistry letters 10, 1173-1179.