Engineering antigen‐specific NK cell lines against the melanoma‐associated antigen tyrosinase via TCR gene transfer
Parlar, Ayhan and Sayitoğlu, Ece Canan and Özkazanç, Didem and Georgoudaki, Anna-Maria and Pamukcu, Cevriye and Aras, Mertkaya and Josey, Benjamin J. and Chrobok, Michael and Branecki, Suzanne and Zahedimaram, Pegah and Ikromzoda, Lolai and Alıcı, Evren and Erman, Batu and Duru, Adil D. and Sütlü, Tolga (2019) Engineering antigen‐specific NK cell lines against the melanoma‐associated antigen tyrosinase via TCR gene transfer. European Journal of Immunology, 49 (8). pp. 1278-1290. ISSN 0014-2980 (Print) 1521-4141 (Online)
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Official URL: http://dx.doi.org/10.1002/eji.201948140
Introduction of Chimeric Antigen Receptors to NK cells has so far been the main practical method for targeting NK cells to specific surface antigens. In contrast, T cell receptor (TCR) gene delivery can supply large populations of cytotoxic T‐lymphocytes (CTL) targeted against intracellular antigens. However, a major barrier in the development of safe CTL‐TCR therapies exists, wherein the mispairing of endogenous and genetically transferred TCR subunits leads to formation of TCRs with off‐target specificity. To overcome this and enable specific intracellular antigen targeting, we have tested the use of NK cells for TCR gene transfer to human cells. Our results show that ectopic expression of TCR α/β chains, along with CD3 subunits, enables the functional expression of an antigen‐specific TCR complex on NK cell lines NK‐92 and YTS, demonstrated by using a TCR against the HLA‐A2‐restricted tyrosinase‐derived melanoma epitope, Tyr368‐377. Most importantly, the introduction of a TCR complex to NK cell lines enables MHC‐restricted, antigen‐specific killing of tumor cells both in vitro and in vivo. Targeting of NK cells via TCR gene delivery stands out as a novel tool in the field of adoptive immunotherapy which can also overcome the major hurdle of “mispairing” in TCR gene therapy.
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