A distinct population of γδ T cells are the dominant lymphocyte subset in human pancreatic ductal adenocarcinoma (PDAC), according to new research. These cells support oncogenesis by suppressing effector T-cell activation, suggesting the potential for novel pancreatic cancer immunotherapies.

The progression of PDAC is associated with immune-suppressive inflammation and a deficiency of effector T cells, stemming in part from leukocyte crosstalk within the tumour microenvironment. γδ T cells have shown contrasting effects on tumorigenesis in different cancers but the exact role of this T-cell subset in PDAC was unknown. Now, following an interest in these cells from work in liver regeneration, George Miller and colleagues specifically examined intrapancreatic γδ T cells.

“Our first preliminary experiment was very provocative. We discovered that γδ T cells were the majority T-cell subset in many human pancreas tumours,” reports Miller. The deletion or depletion of γδ T cells, or inhibition of their recruitment, protected against PDAC in vivo, causing increased infiltration and activation of antitumour T cells. Furthermore, γδ T cells inhibited effector T cells though direct cellular interactions — PDAC-infiltrating γδ T cells in mice and humans showed high expression of PDL1, the ligand for the immune checkpoint protein PD1. Blockade of PDL1 also protected against PDAC in vivo, but only when γδ T cells were present, suggesting that γδ T cells regulate effector T-cells in PDAC and are key sources of checkpoint ligands.

“That γδ T cells mediate T-cell suppression via expression of PDL1 is also novel as the PDL1–PD1 axis was thought to be mediated by tumour cell or myeloid cell interactions with effector T cells,” explains Miller. These findings suggest that the development of biologics targeting γδ T cells could be an attractive strategy for pancreatic cancer immunotherapy. The researchers also plan to investigate the potential suppressive roles of γδ T cells in other types of cancer.