Human γδ T cells in the tumor microenvironment: Key insights for advancing cancer immunotherapy

Abstract

The role of γδ T cells in antitumor responses has gained significant attention due to their major histocompatibility complex (MHC)-independent killing mechanisms, which are functionally distinct from conventional αβ T cells. Notably, γδ tumor-infiltrating lymphocytes (TILs) have been identified as favorable prognostic markers in various cancers. However, the γδ TIL subsets, including Vδ1, Vδ2, and Vδ3, exhibit distinct prognostic implications and phenotypes within the tumor microenvironment (TME). Although the underlying mechanisms remain unclear, recent studies suggest that these subset-specific differences may arise from divergent activation pathways. Vδ1 TILs appear to be mainly activated by γδ T-cell receptor (TCR) signaling, whereas Vδ2 TILs seem to rely on alternative pathways, such as natural killer (NK) receptor-mediated activation. In addition to phenotypic studies, cancer immunotherapies, such as engineered γδ T cells, γδ T-cell engagers, and γδ TCR-based therapies, are under active development. However, despite these advancements, functional heterogeneity and limited persistence within TME remain significant challenges. Overcoming these obstacles could position γδ T-cell therapies as a transformative platform for cancer treatment. Here, we review recent findings on the prognostic significance of human γδ T cells, their phenotypic characteristics, and advances in γδ T-cell therapies, offering valuable insights for the development of novel cancer immunotherapies.

Keywords: Advancements in γδ T-cell therapy; Limitations of γδ T-cell therapy; Phenotypic characteristics of γδ T cells; Prognostic value of γδ T cells; γδ tumor-infiltrating lymphocytes.

Fig. 1

Recent advances in γδ T-cell therapies. Engineered γδ T cells: γδ T cells, known for their allogeneic compatibility, are utilized in adoptive cell therapy, where chimeric antigen receptors (CARs) can be introduced to target tumor-associated antigens (TAAs). These cells can be further engineered to overexpress IL-15, in order to enhance in vivo persistence. Other strategies involve anti-PD-1 antibody–secreting γδ T cells to counteract immunosuppressive tumor microenvironment. Additionally, γδ T cells can be engineered to secrete anti-TAA opsonins, which are fusion proteins combining TAA-targeting single-chain variable fragment (scFv) and the Fc portion of the antibody. These engineered cells also produce stabilized IL-15 (stIL15), a fusion protein of IL-15 with the sushi domain of IL-15Rα, to improve cell persistence. γδ T-cell engagers: γδ T cells can be activated in vivo using various γδ T-cell engagers. Zoledronate, a traditional engager, induces a conformational change in BTN3A1 specifically on tumor cells when conjugated with an anti-TAA antibody. Additionally, anti-BTN3A agonistic antibodies can induce conformational changes in all BTN3A isoforms recognized by Vγ9Vδ2 T cells. Other engager molecules include bispecific antibodies targeting both TAAs and Vγ9Vδ2 TCR, which enhance the tumor-targeting capabilities of Vγ9Vδ2 T cells. γδ TCR-based therapies: Alternative approaches involve equipping conventional αβ T cells with the Vγ9Vδ2 TCR to enhance their tumor-targeting abilities. This can be achieved using γδ TCR-antibody bispecific molecules (GABs), which consist of the Vγ9Vδ2 TCR and an anti-CD3 scFv, or by engineering autologous αβ T cells to express a defined Vγ9Vδ2 TCR (TEGs). TEGs can be further engineered to express NKG2D CAR, thereby enhancing their antitumor responses.