Donor and Recipient HLA Class I Molecule Are Required for Maximum NK Cells Cytotoxicity Reconstitution Post Haploidentical Hematopoietic Stem Cells Transplantation

Background: Our previous report had demonstrated that haploidentical stem cells transplantation (Haplo-SCT) recipients presenting class I for donor inhibitory KIRs promote NK-cell licensing, leading to decreased relapse rates. Hsu and colleagues had showed that both cell intrinsic and -extrinsic HLA cooperate to maintain and adjust NK cell education.

Aim: We hypothesis that donor and recipient HLA class I molecule are required for maximum human NK cells education post haplo-SCT.

Methods: In this study, we compared the cytotoxicity of reconstituting NK cells against K562 cells derived in patients 30-90 days in the first cohort of 76 patients after haplo-SCT. We also addressed whether both of donor and recipient expression of class I ligands for donor inhibitory KIRs could predict lowest relapse rate occurrence in the second cohort of 291 myeloid hematological malignant disease patient.

Results: A longitudinal analysis in the first cohort indicated that donor and recipient HLA class I molecules contribute to NK cell education in patients following haplo-SCT. We compared NK cells exhibiting KIR2DL1, KIR2DL2/KIR2DL3, or KIR3DL1 as their sole receptor, stratifying based on the presence or absence of their ligands in the haplo-SCT donor and/or recipient. HLA-Bw4 contributed by both the donor and the recipient promoted KIR3DL1+ NK cell responsiveness to K562 cells: the highest responsiveness occurred when HLA-Bw4 was available in both, and however lowest NK cells responsiveness occurred when the KIR ligand was absent in both. The educating ligands for KIR2DL1 (HLA-C2) and KIR2DL2 or KIR2DL3 (HLA-C1) contributed similarly to NK cell education: ligand present in both the donor and recipient was associated with the highest reactivity, and similar NK cell responsiveness occurred when the KIR ligand was present in either the donor or the recipient. Multivariate analysis demonstrated in the second haplo-SCT cohort setting, the higher relapse rate was observed when donor KIRs were not ligated by donor class I compared to those donor KIRs ligated by donor class I(HR, 95%CI, 2.406(0.996-5.811), P=0.051). If we considering the donor-host partnerships, the lowest relapse rate was observed when donor KIRs were ligated by both of donor and recipient class I (n =36, 5.74%±4.0% vs. 8.76%±4.5% vs. 18.98%±4.4%, P=0.069 for relapse) compared with where donor KIRs were ligated by donor or recipient class I (n = 158) or where donor KIRs were not ligated by donor and recipient class I (n = 97). Meanwhile, highest leukemia free survival was observed when donor KIRs were ligated by both of donor and recipient class I (n =36) compared with where donor KIRs were ligated by donor or recipient class I (n = 158, 85.8%±5.9% vs. 66.9%±3.9%, P=0.047) or where donor KIRs were not ligated by donor and recipient class I (n = 97, 85.8%±5.9% vs. 68.8%±5.0%, P=0.076).

Conclusion: This study suggests that both of donor and recipient HLA class I molecule are required for maximum NK cells functional reconstitution post haplo-SCT.