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

O. A Koval; Коваль О. А; V. G Subrakova; Субракова В. Г; A. A Nushtaeva; Нуштаева А. А; T. N Belovezhets; Беловежец Т. Н; O. A Troitskaya; Троицкая О. А; M. S Ermakov; Ермаков М. С; M. E Varlamov; Варламов М. Е; A. N Chikaev; Чикаев А. Н; E. V Kuligina; Кулигина Е. В; S. V Kulemzin; Кулемзин С. В; AA. A Gorchakov; Горчаков А. А; A. V Taranin; Таранин А. В; V. A Richter; Рихтер В. А

doi:10.23868/201912034

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

Authors: Koval O.A¹^,2, Subrakova V.G²^,3, Nushtaeva A.A¹, Belovezhets T.N³, Troitskaya O.A¹, Ermakov M.S¹^,2, Varlamov M.E¹^,2, Chikaev A.N³, Kuligina E.V¹, Kulemzin S.V³, Gorchakov A.A²^,3, Taranin A.V²^,3, Richter V.A¹
Affiliations:
1. Institute of Chemical Biology and Fundamental Medicine SB RAS
2. Novosibirsk State University
3. Institute of Molecular and Cellular Biology SB RAS
Issue: Vol 14, No 4 (2019)
Pages: 66-71
Section: Articles
URL: https://genescells.ru/2313-1829/article/view/122213
DOI: https://doi.org/10.23868/201912034
ID: 122213

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Abstract

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 anti-PSMA 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

PSMA, CAR-NK cells, chimeric antigene receptor, lactaptin, PSMA

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References

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

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Abstract

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