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Car-dependent anti-metastatic activity of modified NK cell line YT

Genes & Cells: Vol XIV, №4, 2019, pp: 66-71 DOI: 10.23868/201912034

Authors

O.A. Koval, V.G. Subrakova, A.A. Nushtaeva, T.N. Belovezhets, O.A. Troitskaya, M.S. Ermakov, M.E. Varlamov, A.N. Chikaev, E.V. Kuligina, S.V. Kulemzin, A.A. Gorchakov, A.V. Taranin, V.A. Richter

Adoptive T- and NK-cells transfer with chimeric antigenic receptors (CAR) is considered as a promising anticancer strategy. Chimeric antigenic receptors are artificial molecules that provide activation of the cells carrying them when they contact with a specific antigen to induce cell death. Unlike T cells, NK cells have no T-cell receptors, which prevent “graft-versus-host” disease under allograft transplantation. The aim of this work was to study antimetastatic activity of a double-modified human NK cell line YT — Cyto-CAR-YT-Lact cells carrying CAR to the PSMA protein and expressing antiapoptotic protein lactaptin. The BrCCh4e-134 breast carcinoma line with high PSMA expression was constructed by lentiviral transduction. The YT double modified NK cell line, Cyto-CAR-YT-Lact, expressing functional antiPSMA CAR and carrying a deletion of the Shp-2 gene encoding the Shp-2 protein, a negative regulator of NK cell activation, was used as effector cells. The cytotoxic activity of Cyto-CAR-YT-Lact cells was tested on PSMA-positive BrCCh4e-134 cells and on parental BrCCh4e cell in vitro in real-time mode. The antimetastasis activity of Cyto-CAR-YT-Lact cells was analyzed in SCID and NOD/SCID mice with spontaneously metastases and intravenously transplanted PSMA-positive BrCCh4e-134 cells. Cyto-CAR-YT-Lact cells efficiently reduced the viability of PSMA-positive tumor cells and moderately PSMA-negative target cells in vitro. As a tumor model, we used human breast cancer cells that overexpress PSMA as a transgene and are characterized by metastasis to the mediastinal lymph nodes being transplanted on mice. It was shown that a single intravenous administration of the Cyto-CAR-YT-Lact cells suppressed the development of metastases in the spontaneous metastasis model and when tumor cells were introduced into the bloodstream. The reaction of the primary tumor node to Cyto-CAR-YT-Lact therapy was not detected. Thus, the use of modified NK cells can be considered as a promising therapeutic approach for suppressing metastasis, but not for suppressing the growth of the primary tumor node.

Keywords: CAR-NK cells, chimeric antigene receptor, lactaptin, PSMA.

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