Immunotherapy, in addition to surgery, chemotherapy, and radiotherapy, has now become the fourth pillar of anticancer treatment, with T cell-based immunotherapy being a successful cancer treatment technique. T cells can be separated into two subpopulations based on the expression of T-cell receptors (TCRs). αβ T cells, expressing expressing αβ TCR, recognize peptide antigens, such as those expressed by cancer cells. αβ T cells are the effector cells of adaptive immunity, which exert cytotoxicity in a major histocompatibility complex (MHC)-restricted manner. However, due to the loss of MHC molecules, tumor cells are usually resistant to αβ T cell attacks.
In contrast, γδ T cells, expressing γδ TCR, are effector cells in the innate immune system, which function in an MHC-unrestricted manner, making them ideal mediators for cancer immunotherapy. Recent studies have shown that γδ T cells have potent cytotoxic effects against various types of cancer cells. However, γδ T cells represent only a small fraction of circulating lymphocytes and the clinical benefit is not satisfactory. Currently, some improved approaches, such as bispecific antibodies and CAR-T may break through the limitations of γδ T cells and improve the anti-tumor effect.
Activation of γδ T cells
Human peripheral blood γδ T cells primarily express Vδ2 and Vγ9 chains that are activated upon recognition of phosphorylated antigens (PAGs) such as HMBPP. BTN3A1 is an isoform of the BTN3A (CD277) family that plays an integral role in PAG activation of γδ T cells. BTN3A1 is expressed on the cell surface and is widely expressed, consisting of two immunoglobulin-like extracellular structural domains and an intracellular B30.2 structural domain.
In general, under physiological conditions, the concentration of PAG is not sufficient to stimulate γδ T cells. However, due to metabolic reprogramming, tumor cells exhibit an upregulation of PAG production, which increases the activity of the mevalonate pathway. In addition, PAG concentrations can be pharmacologically increased. Nitrogen-containing bisphosphonates used for the treatment of hypercalcemia or cancer bone metastases, such as pamidronate (Pam) and zoledronate (ZOL), inhibit farnesyl diphosphate (FPP) synthase, the rate-limiting enzyme in the mevalonate pathway. As a result, the concentration of IPP (the upstream metabolite of FPP) increases, thereby activating γδ T cells.
γδ T cells recognize PAG not only by γδ TCR but also by NKG2D receptors for stress-related antigens, and for natural killer cells, which is not restricted by MHC.
Tumor microenvironment and γδ T cells
Several studies have demonstrated the plasticity of γδ T cells, which, upon activation by PAGs, promote the Th1 immune response by secreting TNF-α and IFN-γ. However, γδ T cells can also polarize into cells with properties similar to those of Th2 cells, Th17 cells, or regulatory T cells (Treg).
Tumors include not only cancer cells but also extracellular matrix (ECM), stromal cells (e.g., fibroblasts and mesenchymal stromal cells), vascular networks and immune cells such as T and B cells, NK cells, and various immunosuppressive cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs), all of which constitute the tumor microenvironment (TME).
TME contains various cytokines, chemokines, growth factors, inflammatory mediators, and matrix remodeling enzymes to promote communications among the cells that make up TME. This environment promotes the polarization of γδ T cells into Th17 or Treg-like cells that produce IL-17 and TGF-β, which favor cancer cell proliferation. IL-17-producing γδ T cells induce angiogenesis and support cancer progression, and TGF-β negatively regulates γδ T cells.
Targeting TME can enhance the antitumor effect by activating and improving the cytotoxicity of γδ T cells. Among these TME-targeted therapies, therapeutic antibodies against suppressive immune checkpoint molecules are an effective means to overcome the immunosuppressive effects of TME. The combination of pericytes γδ T cells with immune checkpoint inhibitors is a promising strategy to improve their cytotoxicity, because PAG-stimulated γδ T cells express PD-1 and blocking PD-1 may enhance the antitumor effects of γδ T cells.
New forms of γδ T cell therapy (https://gammadelta-t-therapy.creative-biolabs.com/t-cell-therapy-develop...)
In recent years, several strategies have been proposed to improve the antitumor effect of γδ T-cell immunotherapy.
* The use of bispecific antibodies significantly increases cytotoxicity.
* Chimeric antigen receptor-transduced γδ T cells (CAR-γδT) is another new strategy to overcome the current therapeutic limitations.
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