Immunotherapy Research Group
Research topics
Insufficient effectiveness of conventional cancer therapies has driven the development of strategies that harness the potential of the immune system to fight cancer.
Immunotherapy is based on various approaches that mobilize immune cells to destroy malignant cells. One such approach is adoptive cell therapy (ACT), which involves administering tumor-specific T lymphocytes capable of killing cancer cells.
Advances in cell-engineering technologies have enabled the generation of modified immune cells in vitro, characterized by enhanced cytotoxic activity. To date, six ACT therapies based on genetically engineered patient-derived T lymphocytes (so-called CAR-T cells—chimeric antigen receptor T cells) have been approved for clinical use in selected blood cancers. Further improvements to ACT include identifying more effective effector cells that do not require autologous administration. One promising candidate group is γδ T lymphocytes.
γδ T cells constitute 1–10% of circulating T lymphocytes and are considered enigmatic cells that bridge innate and adaptive immune responses.
This feature makes them more suitable for immunotherapeutic applications than the dominant αβ T lymphocytes, which require antigen processing and presentation by major histocompatibility complex (MHC) molecules. γδ T-cell receptors (γδ TCRs) can directly recognize molecular patterns of cellular pathology (so-called stress antigens) without the need for MHC involvement.
Importantly, the lack of MHC restriction allows allogeneic use of γδ T cells in situations where expansion of autologous T cells is difficult or impossible. Upon activation, γδ T cells secrete interferon gamma (IFN-γ) and tumor necrosis factor alpha (TNF-α)—cytokines well known for their cytotoxic properties. It has been shown that the dominant γδ T-cell subpopulation in blood, containing the Vδ2 chain in the TCR complex, responds to phosphoantigens, which are non-peptide intermediates of the mevalonate and non-mevalonate pathways of isoprenoid biosynthesis.
The second major γδ T-cell subpopulation, containing the Vδ1 chain and found mainly in the skin and mucosal tissues, recognizes molecules present on stressed and cancerous cells, such as MICA/B and UL16-binding proteins. Both γδ T-cell populations also express NKG2D, another receptor that recognizes stress antigens such as MICA/B and powerfully activates anticancer functions.
Extensive preclinical data from mouse studies have demonstrated the effectiveness of γδ T cells derived from blood and expanded in vitro against various tumor types, enabling their further evaluation in early-phase clinical trials.
Key features of γδ T lymphocytes
cytotoxic functions dependent on recognition of “cellular pathology” antigens by γδ TCR and NKG2D receptors
not fully understood ligands for γδ TCRs (in contrast to the well-characterized ligands of NKG2D)
rapid response without the need for antigen presentation (in contrast to αβ T cells)
lack of sensitivity to MHC molecules (in contrast to NK cells)
Despite the identification of certain ligands for the γδ TCR, the mechanisms governing γδ T-cell activation are still not fully understood.
Despite the identification of several γδ TCR ligands, the mechanisms of γδ T-cell activation are still not fully understood. It remains unclear which molecules—beyond the γδ TCR itself—are essential for their activation. Our goal is to investigate γδ TCR-mediated signaling and the mechanisms governing γδ T-cell activation, which may enable the development of more effective effector cells for cancer therapy.
We also plan to genetically modify γδ T cells to enhance their anticancer properties. Our ultimate aim is to develop a patented medicinal product based on γδ T cells, which will reach clinical use and help oncology patients.
Research plan
Using in vitro cultures of blood-derived γδ T cells, we assess their cytotoxic activity against cancer cell lines and primary tumor cells obtained from patients, in order to determine which subpopulation (Vδ2+ or Vδ1+) is best suited for therapeutic applications.
We are creating three-dimensional cancer cell cultures to study and compare the anticancer efficacy of γδ T cells. In the next phase, the effectiveness of these cells will be verified in vivo in a mouse model.