Recipient T Cell Exhaustion and Successful Adoptive Transfer of Haploidentical Natural Killer Cells

Natural killer (NK) cells mediate surveillance for malignancy. In some chemotherapy refractory myeloid leukemia patients, adoptive transfer of NK cells from haploidentical donors can induce remission. We have previously shown that remission induction is linked to NK cell persistence at day +14, but the factors influencing NK cell persistence are unknown. To address this question, patient samples from a phase I trial of National Cancer Institute (NCI) IL-15 in whom either did or did not show NK cell expansion were compared with healthy donor control subjects. Before lymphodepleting chemotherapy, high absolute CD3⁺ count was predictive of patients who failed to expand their haploidentical NK cell graft. Interestingly, both groups had elevated expression of inhibitory receptors and decreased cytokine production compared with control subjects, suggestive of T cell exhaustion among all patients before haploidentical NK cell infusion. At day +14, however, haploidentical NK cell expanders had persistence of recipient CD8⁺ T cells with the most exhausted inhibitory phenotype (either PD-1^high or dual PD-1⁺Tim-3⁺) and elevated expression of T-bet and Eomes compared with NK cell nonexpanders and control subjects. This suggested that maintenance of an exhausted T cell state at day +14 permits haploidentical NK cell expansion and supports further efforts to selectively deplete recipient T cells or modulate their dysfunction.