Can we make a better match or mismatch with KIR genotyping?

Abstract

Natural killer (NK) cell function is regulated by a fine balance between numerous activating and inhibitory receptors, of which killer-cell immunoglobulin-like receptors (KIRs) are among the most polymorphic and comprehensively studied. KIRs allow NK cells to recognize downregulation or the absence of HLA class I molecules on target cells (known as missing-self), a phenomenon that is commonly observed in virally infected cells or cancer cells. Because KIR and HLA genes are located on different chromosomes, in an allogeneic environment such as after hematopoietic stem cell transplantation, donor NK cells that express an inhibitory KIR for an HLA class I molecule that is absent on recipient targets (KIR/KIR-ligand mismatch), can recognize and react to this missing self and mediate cytotoxicity. Accumulating data indicate that epistatic interactions between KIR and HLA influence outcomes in several clinical conditions. Herein, we discuss the genetic and functional features of KIR/KIR-ligand interactions in hematopoietic stem cell transplantation and how these data can guide donor selection. We will also review clinical studies of adoptive NK cell therapy in leukemia and emerging data on the use of genetically modified NK cells that could broaden the scope of cancer immunotherapy. Learning Objectives• To understand the influence of various inhibitory and activating KIR receptors on HSCT outcomes • To understand how these effects may vary by donor source and underlying disease

Natural killer cells in antitumour adoptive cell immunotherapy

“…Early into the journey of NK cell-based immunotherapy, the field recognized a dramatically reduced probability of post-transplant AML relapse in recipients of HLA haplotype-mismatched grafts with KIR ligand incompatibility 53 . Although KIR–HLA genotype-informed donor selection remains an area of active investigation 54 – 57 , evidence suggests a potential benefit of this approach in the setting of T cell-depleted allogeneic haematopoietic stem cell transplantation (alloHSCT) 58 – 66 . Further work is needed to determine whether this strategy can be successfully adopted into NK cell therapy pipelines.…”

Differential Effect of Graft-versus-Host Disease on Survival in Acute Leukemia according to Donor Type

“…One limitation was the study was based on a retrospective registry-based data in Japan. Therefore, there could have been a selection bias and unavailable data, such as a mutation profile for leukemia (36,37), HLA-DPB1 mismatch (10,25), killer immunoglobulin-like receptors (KIR) ligand mismatch (38), and post-transplant maintenance therapy (39,40), which could have affected the GVL effects or relapse rate after HCT. Second, the development of acute and chronic GVHD frequently overlapped, and the treatment intervention and response for acute and chronic GVHD could not be considered to have evaluated the GVL effects.…”

Treatment of recurrent pediatric myelodysplastic syndrome post hematopoietic stem cell transplantation

“…Addition of hypomethylating agents to DLI may provide additional benefit 15 and second HCT should be considered 16–21 . While several novel therapies may alter the future landscape of MDS therapy 22–28 (Table 1), the optimal approach to relapsed pediatric MDS remains unclear. We report the management of a child who relapsed less than 70 days after initial HCT.…”