Background Natural killer (NK) cells play a crucial role in both physiologic and pathologic conditions, including cancer. A number of strategies have been employed to utilize the cytolytic properties of NK cells in the treatment of cancer.1,2 One hurdle to the efficacy of NK-cell based therapy is NK cell infiltration into tumors. 3 The mechanisms NK cells employ for physical migration are not well described.4,5 We recently found that fibroblast activation protein (FAP) is expressed by human NK cells. FAP is a type-II transmembrane serine protease previously thought to primarily be expressed in reactive stromal fibroblasts. FAP plays a role in tissue remodeling and extracellular matrix digestion to facilitate cell migration.6
Methods FAP expression was examined on NK cells by both western blot and immunofluorescence. Compound 60 (CDP60) was used as a specific pharmacological inhibitor of FAP in these assays.
Results We have confirmed that fibroblast activation protein (FAP) is expressed by human NK cells, using both western blot and immunofluorescence. To examine the role of FAP in NK cells we find that following inhibition of FAP activity, NK cells demonstrate decreased migration in 3D culture systems, as well as decreased extravasation from the blood vessels of zebrafish.
Conclusions Future studies include generating an FAP knockout NK cell line to verify the role of FAP in NK cells identified using CPD60. These findings suggest that FAP is responsible for NK cell migration and may provide a potential novel mechanism to regulate this process. This role in migration can potentially be exploited to enhance NK cell migration into tumors.
Acknowledgements The Lombardi Comprehensive Cancer Center's Shared Resources, including Flow Cytometry Shared Resource and Microscopy and Imaging Shared Resource
Fayette J, Lefebvre G, Posner M R, Bauman J, Salas S, Even C, Saada-Bouzid E, Seiwert T, Colevas D, Calmels F, Zerbib R, Boyer Chammard A, Cohen R. Results of a phase II study evaluating monalizumab in combination with cetuximab in previously treated recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Ann Oncol. 2018;374:29.
Sarhan D, Brandt L, Felices M, Guldevall K, Lenvik T, Hinderlie P, Curtsinger J, Warlick E, Spellman S R, Blazar B R, Weisdorf D J, Cooley S, Vallera D A, Onfelt B, Miller J S. 161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS. Blood Adv. 2018;2:1459–1469.
Zhang Q, Zhang H, Ding J, Liu H, Lu M, Miao Y, Li L, Zheng J. Combination therapy with EPCAM-CAR-NK-92 cells and regorafenib against human colorectal cancer models. J Immunol Res 2018;2018:4263520.
Wennerberg E, Kremer V, Childs R, Lundqvist A. CXCL10-induced migration of adoptively transferred human natural killer cells toward solid tumors causes regression of tumor growth in vivo. Cancer Immunol Immunother 2014;64:225–235.
Kameritsch P, Renkawitz J. Principles of Leukocyte Migration Strategies. Trends Cell Biol. 2020;30:818–832.
Fitzgerald A, Weiner LM. The role of fibroblast activation protein in health and malignancy. Cancer metastasis reviews 2020;39:783–803.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.