NKG2D-CAR memory T cells target pediatric T-cell acute lymphoblastic leukemia in vitro and in vivo but fail to eliminate leukemia initiating cells

Front Immunol. 2023 Oct 18:14:1187665. doi: 10.3389/fimmu.2023.1187665. eCollection 2023.

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.

Keywords: NKG2D; NKG2D CAR T cells; T cell lymphoblastic leukemia; leukemia initiating cells; pediatric acute leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Child
  • Humans
  • Memory T Cells
  • Mice
  • NK Cell Lectin-Like Receptor Subfamily K / metabolism
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / therapy
  • Receptors, Chimeric Antigen*

Substances

  • NK Cell Lectin-Like Receptor Subfamily K
  • Receptors, Chimeric Antigen

Grants and funding

This work was supported by a grant from the Instituto de Salud Carlos III to LF PI21/01049, the II and V awards from UNOENTRECIENMIL Foundation, and a grant from CRIS FOUNDATION to Beat Cancer as part of the projects “Cell therapy based on NKG2D-CAR for pediatric leukemia” and “NKG2D-CAR as treatment for pediatric patients suffering from acute leukemia and juvenile myelomonocytic leukemia”. AF, MI-N, AN-Z and CF have been supported by Personnel research grants from CRIS Foundation to beat cancer. CM has been supported by Personnel PhD student grants from the Instituto de Salud Carlos III (ISCIII), PFIS (FI19/00176). MVG is funded by grant PID2021-123795OB-I00 from the Spanish Ministry of Science and Innovation [Ministerio de Ciencia e Innovación (MCIN)/Agencia Estatal de Investigación (AEI) / 10.13039/501100011033 and European Regional Development Fund (ERDF)-A way of making Europe] and belongs to cancer-Hub CSIC. MI lab is funded by grant PID2020-114148RB-I00 from the Spanish Ministry of Science and Innovation MCIN/AEI/10.13039/501100011033,which was in part granted with FEDER funding (EC).