KIRandHLAGenotypes Are Associated with Disease Progression and Survival following Autologous Hematopoietic Stem Cell Transplantation for High-Risk Neuroblastoma

Abstract

Purpose: NK cells exhibit cytotoxicity against neuroblastoma. Gene polymorphisms governing NK cell function, therefore, may influence prognosis. Two highly polymorphic genetic loci instrumental in determining NK cell responses encode the NK cell killer immunoglobulin-like receptors (KIR) and their class I human leukocyte antigen (HLA) ligands. We hypothesized that patients with a "missing ligand" KIR-HLA compound genotype may uniquely benefit from autologous hematopoietic stem cell transplantation (HSCT). Experimental Design: One hundred sixty-nine patients treated with autologous HSCT for stage IV neuroblastoma underwent KIR and HLA genotyping. Patients were segregated according to the presence or absence of HLA ligands for autologous inhibitory KIR. Univariate and multivariate analyses were done for overall and progression-free survival. Results: Sixty-four percent of patients lacked one or more HLA ligands for inhibitory KIR. Patients lacking a HLA ligand had a 46% lower risk of death [hazard ratio, 0.54; 95% confidence interval (95% CI), 0.35-0.85; P = 0.007] and a 34% lower risk of progression (hazard ratio, 0.66; 95% CI, 0.44-1.0; P = 0.047) at 3 years compared with patients who possessed all ligands for his/her inhibitory KIR. Among all KIR-HLA combinations, 16 patients lacking the HLA-C1 ligand for KIR2DL2/KIR2DL3 experienced the highest 3-year survival rate of 81% (95% CI, 64-100). Survival was more strongly associated with "missing ligand" than with tumor MYCN gene amplification. Conclusion: KIR-HLA immunogenetics represents a novel prognostic marker for patients undergoing autologous HSCT for high-risk neuroblastoma. (Clin Cancer Res 2009;15(23):7330-4) Neuroblastoma is the most frequently diagnosed cancer in infants and is the most common extracranial solid tumor in childhood (1). Prognosis varies, and risk assessment is based on several clinical and biological features, including age, stage at diagnosis, histopathology, and biomarkers of tumor aggressiveness (MYCN status, histology, and DNA ploidy; refs. 2,3). The risk of tumor progression likely depends not only on tumor biology but also on the host immune response. NK cells are capable of inhibiting colony formation of human neuroblastoma cells (4-7), and infusion of NK cells into nonobese diabetic/severe combined immunodeficient mice bearing human metastatic neuroblastoma leads to a significant improvement in overall survival (4). Based on recent advances linking NK cell function to NK cell genetics (8-11), we hypothesized that variations in genes responsible for regulating NK function may affect clinical outcomes for patients with neuroblastoma.The killer immunoglobulin-like receptor (KIR) gene cluster consists of 15 genes that encode both inhibitory and activating NK cell surface receptors instrumental in governing NK cell function. The similarly polymorphic human leukocyte antigen (HLA) class I gene loci encode three ligand groups for inhibitory KIR: HLA for KIR2DL2/KIR2DL3, HLA for KIR2DL1, and HLA for 12KIR3DL1. Ligation of inhi...

KIR and HLA Genotypes Predictive of Low-Affinity Interactions Are Associated with Lower Relapse in Autologous Hematopoietic Cell Transplantation for Acute Myeloid Leukemia

“…Patients with KIR and HLA class I genotypes predictive of low-affinity interactions and weak NK cell licensing and inhibition (26,30,32) experience lower relapse than patients with KIR and HLA genotypes predictive of high-affinity interactions and potent NK cell licensing and inhibition. These findings are consistent with an autologous NK cell GVL effect (39,63) and support a model of NK cell reactivity whereby low-affinity inhibitory KIR and HLA interactions tip the balance in favor of licensing and activation, whereas high-affinity inhibitory KIR and HLA interactions tip the balance in favor of inhibition.…”

“…There was a trend of decreasing relapse with increasing copy number of HLA-Bw4-80Thr with KIR3DL1. (39). To our knowledge, we are the first to report a benefit of a predicted low-affinity KIR3DL1 and HLA-Bw4 interaction beyond that of missing ligand.…”

“…Importantly, changes in the environment in various disease settings result in the recruitment of specific NK cell subsets, allowing for greater disease control among certain patients (30,(35)(36)(37)(38). In AHCT for neuroblastoma, the presence of a "missing ligand" for inhibitory KIR was associated with improved survival, suggesting that normally hyporesponsive unlicensed NK cells are specifically recruited to control disease in this setting (39). In HLA-matched T cell-depleted alloHCT for hematologic malignancies, both unlicensed hyporesponsive inhibitory KIR-expressing NK cell subsets and licensed normally inhibited NK cell subsets in donor and recipient gain responsiveness after transplantation (37).…”

Neuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR 2DS2 treated by long-term infusion of anti-GD2 antibody ch14.18/CHO show higher ADCC levels and improved event-free survival

“…Furthermore, clinical studies with the murine anti-GD 2 Ab 3F8 or humanized immunocytokine hu14.18-IL-2 demonstrated superior clinical outcome in patients missing inhibitory KIRL. [17][18][19] Similar observations were made in lymphoma patients treated with rituximab. 20 Extending on these results, interactions of activating KIR/KIRL has been recently studied in a number of malignancies.…”

“…8 In treatment of NB with the murine anti-GD 2 Ab 3F8 or humanized immunocytokine hu14.18-IL-2, mismatch of inhibitory KIRL was associated with improved clinical outcome. [17][18][19] These observations were also made in lymphoma patients treated with rituximab suggesting KIR/ KIRL-dependent effects in NK-mediated tumor cell lysis. 20 Surprisingly, in the present study we did not find significant differences in ADCC and EFS between matched and mismatched inhibitory KIR/KIRL genotypes in our patient cohort (data not shown), indicating only a minor role for exclusive consideration of the 2DL3/HLA-C1 and 3DL1/HLA-Bw4 KIR/KIRL repertoire.…”