T cells deficient in diacylglycerol kinase ζ are resistant to PD-1 inhibition and help create persistent host immunity to leukemia

Efforts to improve the efficacy of adoptive T-cell therapies and immune checkpoint therapies in myelogenous leukemia are desired. In this study, we evaluated the antileukemia activity of adoptively transferred polyclonal cancer antigen-reactive T cells deficient in the regulator diacylglycerol kinase zeta (DGKz) with or without PD-1/PD-L1 blockade. In the C1498 mouse model of myeloid leukemia, we showed that leukemia was eradicated more effectively in DGKz-deficient (DGKz/) mice than wild-type mice. T cells transferred from DGKz-deficient mice to wild-type tumor-bearing recipients conferred this benefit. Leukemia clearance was similar to mice treated with anti-PD-L1. Strikingly, we found that the activity of adoptively transferred DGKz/ T cells relied partly on induction of sustainable host T-cell immunity. Transferring DGKz-deficient T cells increased the levels of IFNg and other cytokines in recipient mice, especially with coadministration of anti-PD-L1. Overall, our results offered evidence that targeting DGKz may leverage the efficacy of adoptive T-cell and immune checkpoint therapies in leukemia treatment. Furthermore, they suggest that DGKz targeting might decrease risks of antigen escape or resistance to immune checkpoint blockade.