Camelid-derived Tcell engagers harnessing human γδ T cells as promising antitumor immunotherapeutic agents

Eur J Immunol. 2024 Aug;54(8):e2350773. doi: 10.1002/eji.202350773. Epub 2024 May 28.

Abstract

In the last decade, there has been a surge in developing immunotherapies to enhance the immune system's ability to eliminate tumor cells. Bispecific antibodies known as T cell engagers (TCEs) present an attractive strategy in this pursuit. TCEs aim to guide cytotoxic T cells toward tumor cells, thereby inducing a strong activation and subsequent tumor cell lysis. In this study, we investigated the activity of different TCEs on both conventional alpha-beta (αβ) T cells and unconventional gamma delta (γδ) T cells. TCEs were built using camelid single-domain antibodies (VHHs) targeting the tumor-associated antigen CEACAM5 (CEA), together with T cell receptor chains or a CD3 domain. We show that Vγ9Vδ2 T cells display stronger in vitro antitumor activity than αβ T cells when stimulated with a CD3xCEA TCE. Furthermore, restricting the activation of fresh human peripheral T cells to Vγ9Vδ2 T cells limited the production of protumor factors and proinflammatory cytokines, commonly associated with toxicity in patients. Taken together, our findings provide further insights that γδ T cell-specific TCEs hold promise as specific, effective, and potentially safe molecules to improve antitumor immunotherapies.

Keywords: T cell engager; activation; cancer; immunotherapy; γδ T lymphocyte.

MeSH terms

  • Animals
  • Antibodies, Bispecific* / immunology
  • Carcinoembryonic Antigen / immunology
  • Cell Line, Tumor
  • Humans
  • Immunotherapy / methods
  • Lymphocyte Activation* / immunology
  • Neoplasms / immunology
  • Neoplasms / therapy
  • Receptors, Antigen, T-Cell, alpha-beta / immunology
  • Receptors, Antigen, T-Cell, gamma-delta* / immunology
  • Single-Domain Antibodies / immunology
  • T-Lymphocytes, Cytotoxic / immunology

Substances

  • Receptors, Antigen, T-Cell, gamma-delta
  • Antibodies, Bispecific
  • Single-Domain Antibodies
  • Receptors, Antigen, T-Cell, alpha-beta
  • Carcinoembryonic Antigen