Vγ9Vδ2 T Cells: Can We Re-Purpose a Potent Anti-Infection Mechanism for Cancer Therapy?

Abstract

Cancer therapies based on in vivo stimulation, or on adoptive T cell transfer of Vγ9Vδ2 T cells, have been tested in the past decades but have failed to provide consistent clinical efficacy. New, promising concepts such as γδ Chimeric Antigen Receptor (CAR) -T cells and γδ T-cell engagers are currently under preclinical evaluation. Since the impact of factors, such as the relatively low abundance of γδ T cells within tumor tissue is still under investigation, it remains to be shown whether these effector T cells can provide significant efficacy against solid tumors. Here, we highlight key learnings from the natural role of Vγ9Vδ2 T cells in the elimination of host cells bearing intracellular bacterial agents and we translate these into the setting of tumor therapy. We discuss the availability and relevance of preclinical models as well as currently available tools and knowledge from a drug development perspective. Finally, we compare advantages and disadvantages of existing therapeutic concepts and propose a role for Vγ9Vδ2 T cells in immune-oncology next to Cluster of Differentiation (CD) 3 activating therapies.

Tumor resistance mechanisms and their consequences on γδ T cell activation

“…79 Although the number of Vδ2 TILs is lower than the number of Vδ1 TILs in some tumor entities, Vδ2 TILs are a very interesting effector cell population for T cell-based immunotherapy as extensively summarized in recent reviews. [80][81][82] The interest is based on the capacity of Vδ2 T cells to present soluble proteins and cell debris to CD8 αβ T cells by a proteasome-dependent cross-presentation pathway, [83][84][85] to recognize phosphorylated antigen (PAg) released by tumor cells in a HLA-unrestricted manner and their reduced potential to cause graft versus host disease. 36,86,87 The frequency, phenotype and functions of γδ TILs are presumably influenced by genetic differences between tumor cells, polymorphisms of regulatory genes, exposure to certain pathogens (eg intestinal microbiome) and TME.…”

“…63,171 In sum, galectin-1, 3, and 9 play an important role in the interac- γδ T cell-based immunotherapies is summarized extensively in different reviews. 80,82,199,200 Briefly, although the application of n-BP or PAg ± γδ T cells is well tolerated in these clinical trials, limited promising results have been delivered. Strikingly, a complete remission has been shown in 4 patients with hematological malignancies after adoptive transfer of haploidentical γδ T cells, and in one patient with renal-carcinoma-derived lung metastases after adoptive transfer of autologous γδ T cells.…”

Meta-analysis reveals consistent immune response patterns in COVID-19 infected patients at single-cell resolution

“…However, these groups of marker genes highlight two cell subpopulations next to each other, Supplementary Figure S4 . It is known that Vγ9Vδ2 T cells are the major subset of γδ T cells in human PBMCs 12 . According to the marker knowledge of γδ T cells [12][13][14] , we define the TRGV9 + TRDV2 + subpopulation as Vγ9Vδ2 T cells and other CD161(KLRB1) + TRGC1 + TRGC2 + cells as γδ T cells.…”

“…It is known that Vγ9Vδ2 T cells are the major subset of γδ T cells in human PBMCs 12 . According to the marker knowledge of γδ T cells [12][13][14] , we define the TRGV9 + TRDV2 + subpopulation as Vγ9Vδ2 T cells and other CD161(KLRB1) + TRGC1 + TRGC2 + cells as γδ T cells. The γδ T cells also express canonical γδ T cell markers CCR5, CCR6 15 as well as SLC4A10 16 and TRAV1-2 17 , which are known as Mucosal-associated invariant T (MAIT) cell markers.…”

An Update on the Molecular Basis of Phosphoantigen Recognition by Vγ9Vδ2 T Cells

“…In summary, Vγ9Vδ2 T cells can sense the metabolic changes of transformed [ 32 ], infected [ 40 ], [ 29 ] or drug-treated host cells via their TCR [ 31 , 32 ]. This reactivity can be harnessed clinically as the remission of certain tumor entities after Vγ9Vδ2 T cell activation has been observed (reviewed in [ 41 , 42 ]). Furthermore, Vγ9Vδ2 T cells can support anti-bacterial immunity in preclinical mouse and primate models, including the possibility of PAg-based vaccines against tuberculosis as shown for non-human primates [ 43 , 44 ].…”