AUTHOR=Ibáñez-Navarro Marta , Fernández Adrián , Escudero Adela , Esteso Gloria , Campos-Silva Carmen , Navarro-Aguadero Miguel Ángel , Leivas Alejandra , Caracuel Beatriz Ruz , Rodríguez-Antolín Carlos , Ortiz Alejandra , Navarro-Zapata Alfonso , Mestre-Durán Carmen , Izquierdo Manuel , Balaguer-Pérez María , Ferreras Cristina , Martínez-López Joaquín , Valés-Gómez Mar , Pérez-Martínez Antonio , Fernández Lucía TITLE=NKG2D-CAR memory T cells target pediatric T-cell acute lymphoblastic leukemia in vitro and in vivo but fail to eliminate leukemia initiating cells JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1187665 DOI=10.3389/fimmu.2023.1187665 ISSN=1664-3224 ABSTRACT=Introduction

Refractory/relapsed pediatric acute leukemia are still clinically challenging and new therapeutic strategies are needed. Interactions between Natural Killer Group 2D (NKG2D) receptor, expressed in cytotoxic immune cells, and its ligands (NKG2DL), which are upregulated in leukemic blasts, are important for anti-leukemia immunosurveillance. Nevertheless, leukemia cells may develop immunoescape strategies as NKG2DL shedding and/or downregulation.

Methods

In this report, we analyzed the anti-leukemia activity of NKG2D chimeric antigen receptor (CAR) redirected memory (CD45RA-) T cells in vitro and in a murine model of T-cell acute lymphoblastic leukemia (T-ALL). We also explored in vitro how soluble NKG2DL (sNKG2DL) affected NKG2D-CAR T cells’ cytotoxicity and the impact of NKG2D-CAR T cells on Jurkat cells gene expression and in vivo functionality.

Results

In vitro, we found NKG2D-CAR T cells targeted leukemia cells and showed resistance to the immunosuppressive effects exerted by sNKG2DL. In vivo, NKG2D-CAR T cells controlled T cell leukemia burden and increased survival of the treated mice but failed to cure the animals. After CAR T cell treatment, Jurkat cells upregulated genes related to proliferation, survival and stemness, and in vivo, they exhibited functional properties of leukemia initiating cells.

Discussion

The data here presented suggest, that, in combination with other therapeutic approaches, NKG2D-CAR T cells could be a novel treatment for pediatric T-ALL.