Activated naive gamma delta T cells accelerate deep molecular response to BCR-ABL inhibitors in patients with chronic myeloid leukemia

Tyrosine kinase inhibitors (TKIs) that target BCR-ABL are the frontline treatments in chronic myeloid leukemia (CML). Growing evidence has shown that TKIs also enhance immunity. Since gamma-delta T (gamma delta T) cells possess the potent anticancer capability, here we investigated the potential involvement of gamma delta T cells in TKI treatments for CML. We characterized gamma delta T cells isolated from chronic-phase CML patients before and during TKI treatments. gamma delta T expression increased significantly in CML patients who achieved major molecular response (MMR) and deep molecular response (DMR). Their V delta 2 subset of gamma delta T also expanded, and increased expression of activating molecules, namely IFN-gamma, perforin, and CD107a, as well as gamma delta T cytotoxicity. Mechanistically, TKIs augmented the efflux of isopentenyl pyrophosphate (IPP) from CML cells, which stimulated IFN-gamma production and gamma delta T expansion. Notably, the size of the IFN-gamma(+) naive gamma delta T population in TKI-treated CML patients was strongly correlated with their rates to reach DMR and with the duration on DMR. Statistical analysis suggests that a cutoff of 7.5% IFN-gamma(+) naive subpopulation of gamma delta T in CML patients could serve as a determinant for MR4.0 sustainability. Our results highlight gamma delta T cells as a positive regulator for TKI responses in CML patients.