Donor Natural Killer Cell Allorecognition of Missing Self in Haploidentical Hematopoietic Transplantation for Acute Myeloid Leukemia: Challenging Its Predictive Value.
Authors: Ruggeri Loredana , Mancusi Antonella , Capanni Marusca , Urbani Elena , Carotti Alessandra , Aloisi Teresa , Stern Martin , Perruccio Katia , Burchielli Emanuela , Topini Fabiana , Bianchi Erika , Aversa Franco , Martelli Massimo F. , Velardi Andrea 
Published: April 2020

Abstract
In haploidentical transplants that are KIR ligand mismatched in the GvH direction, functional donor NK-cells that express as their sole inhibitory receptor for self, a KIR for the HLA-class-I group which is absent in the recipient, sense the missing expression of the self class-I ligand on allogeneic targets and mediate alloreactions. In a limited series of transplants donor-vs-recipient NK-cell alloreactivity reduced the risk of AML relapse and markedly improved EFS (Ruggeri L, Science 2002). Here, we analyzed 112 AML patients transplanted from NK-alloreactive (n=51) or non-NK-alloreactive (n=61) haploidentical donors. NK-alloreactive donors possessed: HLA-class-I KIR ligand(s) which were missing in the recipients, KIR gene(s) for missing self recognition on recipient targets, and alloreactive NK-clones against recipient targets. Transplantation from NK-alloreactive donors was associated with: significantly lower relapse rate in patients transplanted in CR (3% vs 47%) (P&lt;0.003); decrease infectious mortality which was more evident in patients transplanted in relapse (P=0.1); better EFS in patients transplanted in relapse (34% vs 6%, P=0.04) and in remission (67% vs 18%, P=0.02); reduced risk of relapse or death (relative risk vs non-NK-alloreactive donor: 0.48 [95% CI 0.29–0.78], P&lt;0.001). Recently, an additional algorithm, termed the “missing ligand” model, has been proposed for predicting favorable outcomes not only in haploidentical (Leung W, JI 2004; JI 2005) but also in matched sibling (Hsu KC, Blood 2005) and in unrelated donor transplants (Hsu KC, BBMT 2006). The “missing-ligand” model includes all donor-recipient pairs in whom there is a mismatch between KIR(s) in the donor and HLA molecule(s) in the recipient. Consequently, the model includes all KIR ligand-mismatched transplants because they are all associated with a missing KIR ligand in the recipient, and KIR ligand-matched transplants from donors possessing “extra” KIR(s) for which neither donor nor recipient have HLA ligand(s). Therefore, in the same series of patients we tested the “missing ligand” model. The first step was to divide our 61 non-NK alloreactive (KIR ligand-matched) donor-recipient pairs according to the number of KIR ligands in donor and recipient, i.e., three KIR ligands (29 patients; 15 in remission, 14 in relapse at transplant) vs fewer than three (32 patients; 16 in remission, 16 in relapse at transplant). EFS did not differ in each sub-group. Both curves indicated worse survival than after transplantation from NK-alloreactive donors. The second step was to group the above 32 “missing ligand” transplants and all 51 KIR ligand-mismatched transplants (which corresponded to all our NK-alloreactive transplants). We analyzed EFS in this pool of 83 patients (46 in remission, 37 in relapse at transplant) against EFS in 29 patients with no missing ligand (15 in remission, 14 in relapse at transplant). No significant difference emerged. EFS in the “missing ligand” cohort was worse than after transplantation from NK-alloreactive donors. Therefore, the present analysis leaves no doubt that KIR ligand mismatches, i.e., donor NK cell recognition of “missing self” on recipient targets, are essential for triggering powerful NK cell alloreactions that impact beneficially on transplantation outcomes.