Hematological malignancies—including leukemia, lymphoma, myelodysplastic syndromes (MDS), and multiple myeloma—remain difficult to manage due to frequent relapse and post-transplant complications such as graft-versus-host disease. Among the emerging immunotherapeutic strategies, γδ T cells stand out for their ability to recognize tumor cells without relying on MHC presentation, offering a promising avenue for effective and low-toxicity treatment. Highlighting recent advances in this field, Blood Science recently presented a focused analysis on the immunobiology and therapeutic potential of γδ T cells in hematologic cancers.Study Focus and Methods
The authors conducted a comprehensive synthesis of existing literature, experimental data, and ongoing clinical trials to evaluate the roles of γδ T cell subsets in antitumor immunity, viral defense post-HSCT, and their therapeutic implications. Emphasis was placed on mechanistic pathways, immunological functions, therapeutic barriers within the tumor microenvironment, and advances in γδ T cell engineering.
Subset Classification and Antigen Recognition
Human γδ T cells are subdivided into Vδ1, Vδ2, and Vδ3 subsets based on their TCR chain composition. Vγ9Vδ2 T cells are the predominant population in peripheral blood and recognize phosphoantigens (PAgs) such as HMBPP and IPP through a mechanism involving butyrophilin molecules (BTN3A1 and BTN2A1). Their activation can be enhanced using agents like zoledronate. In contrast, Vδ1 T cells reside in mucosal tissues and recognize lipid antigens presented by CD1d. These subsets demonstrate specialized functions in immune surveillance and cytotoxicity, reinforcing their therapeutic versatility.
Results and Mechanistic Insights
γδ T cells exert antitumor activity through direct cytotoxicity mediated by TCR engagement, natural killer receptors (NKG2D), and the perforin/granzyme pathway. They also secrete cytokines such as IFN-γ and TNF-α and can trigger antibody-dependent cellular cytotoxicity (ADCC), thereby enhancing the efficacy of monoclonal antibodies. Furthermore, γδ T cells regulate immune responses by activating NK cells, assisting B cell antibody class switching, and engaging with αβ T cells. Post-HSCT, Vδ2-negative γδ T cells have shown effectiveness against CMV and EBV infections, adding an antiviral dimension to their profile.
Nevertheless, persistent exposure to tumor-derived antigens and the immunosuppressive environment within hematologic malignancies can lead to γδ T cell exhaustion. Tumor-associated macrophages, regulatory T cells, and MDSCs release inhibitory cytokines such as IL-10 and TGF-β, promoting the differentiation of γδ T cells into suppressive subsets like γδTregs or IL-17-producing γδT17 cells. Upregulation of immune checkpoint molecules such as PD-1, TIM-3, and CTLA-4 further diminishes their cytotoxic function, posing significant hurdles to therapeutic success.
Clinical Evidence and Therapeutic Exploration
In leukemia, higher γδ T cell levels after transplantation have been associated with lower relapse and better survival outcomes. Trials using zoledronate and IL-2 for in vivo expansion have shown partial responses in AML, with improved outcomes when combined with haploidentical donor cells. In lymphoma and multiple myeloma, early studies with aminobisphosphonates or synthetic phosphoantigens demonstrated safety but limited efficacy, indicating the need for refinement.
Newer approaches include agonist antibodies like ICT01, which activates Vγ9Vδ2 T cells via BTN3A and showed a 30% disease control rate in the EVICTION trial. Bispecific antibodies targeting CD1d or CD123 have enhanced cytotoxicity while minimizing off-target effects. Off-the-shelf allogeneic products like INB-100 achieved complete remission in AML without GvHD. CAR-modified γδ T cells and γδ TCR-engineered αβ T cells are also being tested in early trials with promising safety and efficacy across multiple hematologic malignancies.
Conclusion
γδ T cells hold substantial promise as therapeutic agents in hematological malignancies. Their innate MHC-unrestricted tumor recognition, dual immune functionality, and reduced risk of GvHD make them ideal candidates for next-generation immunotherapy. However, clinical application is limited by their low frequency, functional heterogeneity, and sensitivity to the immunosuppressive tumor environment. Future advancements depend on overcoming these limitations through genetic modification, combination therapies, and strategic manipulation of the tumor milieu. With ongoing trials and biotechnological innovations, γδ T cells are positioned to become a vital component of the immunotherapeutic arsenal in hematologic cancer care.
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