Role of NKG2D Ligands and Receptor in Haploidentical Related Donor Hematopoietic Cell Transplantation.

The recurrence of malignancy after hematopoietic cell transplantation (HCT) is the primary cause of transplant failure. The NKG2D axis is a powerful pathway for anti-tumor responses, but its role in the control of malignancy after HCT is not well-defined. We tested the hypothesis that gene variation of the NKG2D receptor and its ligands MICA and MICB affect relapse and survival in 1,629 patients who received a haploidentical HCT for the treatment of a malignant blood disorder. Patients and donors were characterized for MICA residue 129 and the exon 5 short tandem repeat (STR), and MICB residues 52, 57, 98, 189. Donors were additionally defined for NKG2D residue 72. Mortality was higher in patients with MICB-52Asn relative to 52Asp (HR 1.83 [95% CI 1.24-2.71; P = 0.002]) and lower with MICA STR-mismatching relative to STR-matching (HR 0.66 [95% CI 0.54-0.79; P = 0.00002]). Relapse was lower with NKG2D-72Thr donors relative to 72Ala (relapse HR 0.57 [95% CI 0.35-0.91; P = 0.02]). The protective effects of patient MICB-52Asp with donor MICA STR-mismatching and NKG2D-72Thr were enhanced when all three features were present. The NKG2D ligand/receptor pathway is a transplantation determinant. The immunobiology of relapse is defined by the concerted effects of MICA, MICB and NKG2D germline variation. Consideration of NKG2D ligand/receptor pairings may improve survival for future patients.