Eradication of CD48-positive tumors by selectively enhanced YTS cells harnessing the lncRNA NeST

Rebecca Kotzur; Natan Stein; Shira Kahlon; Orit Berhani; Batya Isaacson; Ofer Mandelboim

doi:10.1016/j.isci.2023.107284

Eradication of CD48-positive tumors by selectively enhanced YTS cells harnessing the lncRNA NeST

iScience. 2023 Jul 5;26(8):107284. doi: 10.1016/j.isci.2023.107284. eCollection 2023 Aug 18.

Authors

Rebecca Kotzur¹, Natan Stein¹, Shira Kahlon¹, Orit Berhani¹, Batya Isaacson¹, Ofer Mandelboim¹

Affiliation

¹ The Lautenberg Center for Immunology and Cancer Research, the Hebrew University, Medical School Hadassah Ein Karem, Israel, Jerusalem.

Abstract

Natural killer (NK) cells are currently used in clinical trials to treat tumors. However, such therapies still suffer from problems such as donor variability, reproducibility, and more, which prevent a wider use of NK cells therapeutics. Here we show a potential immunotherapy combining NK cell-mediated tumor eradiation and long non-coding (lnc) RNAs. We overexpressed the interferon (IFN) $γ$ secretion-enhancing lncRNA nettoie Salmonella pas Theiler's (NeST) in the NK cell-like cell line YTS. YTS cells express the co-stimulatory receptor 2B4 whose main ligand is CD48. On YTS cells, 2B4 functions by direct activation. We showed that NeST overexpression in YTS cells resulted in increased IFN $γ$ release upon interaction with CD48 (selectively enhanced (se)YTS cells). Following irradiation, the seYTS cells lost proliferation capacity but were still able to maintain their killing and IFN $γ$ secretion capacities. Finally, we demonstrated that irradiated seYTS inhibit tumor growth in vivo. Thus, we propose seYTS cells as off-the-shelve therapy for CD48-expressing tumors.

Keywords: Cancer; Cellular therapy; Components of the immune system.