Gamma delta T cells in cancer therapy: from tumor recognition to novel treatments

Abstract

Traditional immunotherapies mainly focus on αβ T cell-based strategies, which depend on MHC-mediated antigen recognition. However, this approach poses significant challenges in treating recurrent tumors, as immune escape mechanisms are widespread. γδ T cells, with their ability for MHC-independent antigen presentation, offer a promising alternative that could potentially overcome limitations observed in traditional immunotherapies. These cells play a role in tumor immune surveillance through a unique mechanism of antigen recognition and synergistic interactions with other immune effector cells. In this review, we will discuss the biological properties of the Vδ1 and Vδ2 T subsets of γδ T cells, their immunomodulatory role within the tumor microenvironment, and the most recent clinical advances in γδ T cell-based related immunotherapies, including cell engaging strategies and adoptive cell therapy.

Keywords: CAR-γδ T cell; adoptive cell therapy; gamma delta T cell; immunotherapy; tumor microenvironment.

Figure 1

Major receptor-ligand recognition between Vδ2/Vδ1 T cells and tumor cells. Recognition of phosphoantigens by the human Vγ9Vδ2 TCR mainly depends on the synergistic action of BTN3A1/BTN2A1. Vδ2 T cells also recognize a complex of F1-ATPase bound to ApoAI and MutS homolog 2 (MSH2). Nectin-2 from tumor cells can also activate Vδ2 T cells by binding to DNAM-1. The Vδ1 TCR recognizes CD1d and its presented lipids, and its expression of NKp30 and NKp44 receptors can bind to ligands B7-H6. In addition to this, NKG2D receptors expressed on Vδ2 and Vδ1 T cells both recognize MICA/B and ULBP molecular ligands.

Figure 2

The role of γδ T cell in tumor microenvironment. Activation of γδ T cells induces tumor cell apoptosis primarily through the perforin-granzyme mechanism, Fas/FasL, and TRAIL pathways. Additionally, γδ T cells eliminate tumor cells by releasing cytokines such as IFN-γ and TNF-α, synergizing with the activation of αβ T cells and NK cells and promoting the conversion of antibodies in B cells as well as the antigen-presenting role of DC cells. In certain instances, γδ T cells differentiate into γδ T17 or γδ Treg cells, which secrete IL-17, IL-10, and TGF-β to facilitate the proliferation of tumor cells, playing an immunosuppressive role. Tumor-derived exosomes (TDE), immunosuppressive receptors have also been shown to modulate γδ T cell immunoregulation in TME.

Figure 3

Cancer immunotherapy with γδ T cells. (A) Agonist antibodies targeting BTN3A1. (B) Bispecific T cell engagers. (C) CAR-γδ T cells.