Targeting HLA-E-overexpressing cancers with a NKG2A/C switch receptor Journal Article
| Authors: | Sætersmoen, M.; Kotchetkov, I. S.; Torralba-Raga, L.; Mansilla-Soto, J.; Sohlberg, E.; Krokeide, S. Z.; Hammer, Q.; Sadelain, M.; Malmberg, K. J. |
| Article Title: | Targeting HLA-E-overexpressing cancers with a NKG2A/C switch receptor |
| Abstract: | Background: Human leukocyte antigen (HLA)-E is overexpressed by a large proportion of solid tumors, including malignant glioblastoma, and acts as a major checkpoint for NKG2A+ CD8+ T cells and natural killer (NK) cells in the tumor microenvironment and circulation. This axis operates alongside PD-L1 to inhibit effector responses by T and NK cells. Methods: We engineered a chimeric A/C switch receptor, combining the high HLA-E binding affinity of the NKG2A receptor ectodomain with the activating signaling of the NKG2C receptor endodomain. The cytotoxic function of A/C switch-transduced NK and T cells was evaluated against tumor cells with varying levels of HLA-E expression. In vivo efficacy was assessed using a xenograft model of glioblastoma. Findings: A/C switch-transduced NK and T cells exhibited superior and specific cytotoxicity against tumor cells with medium to high HLA-E expression. A/C switch-expressing human T cells demonstrated enhanced anti-tumor function in a glioblastoma xenograft model. The activity of the modified T cells was governed by an equilibrium between A/C switch levels and HLA-E expression, creating a therapeutic window to minimize on-target, off-tumor toxicities. Normal cells remained insensitive to A/C switch T cells, even after interferon (IFN)-γ pretreatment to induce HLA-E expression. Conclusions: The A/C switch receptor effectively targets tumor cells expressing high levels of HLA-E, either alone or in combination with other engineered specificities, to overcome the suppressive NKG2A/HLA-E checkpoint. This approach offers a promising therapeutic strategy with a favorable safety profile for targeting HLA-E-overexpressing tumors. Funding: This work was funded by The Research Council of Norway, the Norwegian Cancer Society, and the National Cancer Institute. © 2024 The Author(s) |
| Keywords: | controlled study; protein expression; unclassified drug; human cell; nonhuman; flow cytometry; binding affinity; cd8+ t lymphocyte; t lymphocyte; mouse; gene overexpression; cancer immunotherapy; animal experiment; animal model; cytotoxicity; in vitro study; tumor xenograft; gamma interferon; glioblastoma; cd4+ t lymphocyte; western blotting; natural killer cell; natural killer cell receptor nkg2a; tumor growth; t lymphocyte activation; peripheral blood mononuclear cell; ketamine; programmed death 1 ligand 1; dexmedetomidine; tumor microenvironment; deterioration; tumor blood flow; meloxicam; adipocyte; lymphocyte receptor; nk cells; hla-e; umbilical vein endothelial cell; human; article; car t cells; pre-clinical research; crispr-cas9 system; nk-92 cell line; k-562 cell line; u-251mg cell line; crispr associated endonuclease cas9; nkg2 receptor family; hla e antigen; natural killer group 2c receptor |
| Journal Title: | Med |
| Volume: | 6 |
| Issue: | 2 |
| ISSN: | 2666-6359 |
| Publisher: | Cell Press |
| Date Published: | 2025-02-14 |
| Start Page: | 100521 |
| Language: | English |
| DOI: | 10.1016/j.medj.2024.09.010 |
| PUBMED: | 39423821 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PDF -- Source: Scopus |
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