Novel KIR:HLA interaction (KIR2DS4:HLA-B*35) predicts patient survival post haploidentical donor transplantation 2252772

Abstract Introduction Haploidentical hematopoietic cell transplantation(haploHCT) has become a mainstay in our clinical care for patients with leukemia. Upon the discovery of activating and inhibitory killer immunoglobulin receptors(KIRs) on NK cells and their cognate human leukocyte antigen(HLA) ligands, algorithms have been developed to enhance a graft versus leukemia effect. However, these do not yield consistent predictions in patient outcomes. We posit that this is due to an incomplete map of the entire KIR:HLA interactome. Methods A combination of in silico protein folding and interactions to determine KIR:HLA reactivity in addition to acoustic force microscopy measuring cell avidity(CA) as a readout for KIR signal strength were used. Cell avidity was determined using monoallelic HLA expressing K562 cell lines along with KIR typed ex vivo expanded peripheral blood NK cells. We then applied the newly discovered interaction to patients who had undergone a single haploHCT at our institution with or without additional NK cell infusions post-transplant. Results We found that KIR2DS4 and HLA-B*35 interact in silico. We confirmed this through CA measurements. We took this interaction and sought to determine if it was clinically significant. When stratifying pediatric and adolescent young adult patients based on their HLA B*35 positivity and the donor KIR2DS4 expression, we delineated a strong correlation to survival (P = 0.061) when donors had two copies KIR2DS4. When patients received haploHCT and additional NK cell addback from donors with two copies of KIR2DS4 they did not die or experience relapse during follow-up, resulting in longer OS(P = 0.016) and RFS(P = 0.001) than patients with donors with one copy KIR2DS4. Conclusion We describe a novel KIR2DS4:HLA-B*35 interaction axis that predicts patient survival and lends strong credence to revisit the previously defined KIR ligands and their signaling. Our approach is immediately clinically implementable and warrants further exploration of the KIR:HLA interactome. Funding Source Edward P Evans Young Investigator Award Topic Categories Transplantation Immunology (TRAN)