Imaging, Diagnosis, Prognosis KIR and HLA Genotypes Are Associated with Disease Progression and Survival following Autologous Hematopoietic Stem Cell Transplantation for High-Risk Neuroblastoma

Purpose: NK cells exhibit cytotoxicity against neuroblastoma. Gene polymorphisms governingNKcell function, therefore,may influence prognosis. Twohighly 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 genotypemayuniquelybenefit fromautologoushematopoietic stemcell transplantation (HSCT). Experimental Design: One hundred sixty-nine patients treatedwith autologousHSCT 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 3year 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 inhibitory KIR by self-HLA class I ligands leads to NK inhibition (12). Moreover, NK cells expressing inhibitory KIR for self-HLA class I molecules are preferentially endowed with effector function, ensuring that potentially autoreactive NK cells expressing KIR for non-self HLA (“missing ligand”) are rendered functionally incompetent when they encounter cells lacking their cognate ligand (13–16). Therefore, although ∼60% of individuals have inhibitory KIR receptors for which they lack the HLA class I ligand (“missing Authors' Affiliations: Departments of Medicine and EpidemiologyBiostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York; Immunology Program, Sloan-Kettering Institute for Cancer Research, New York, New York; and Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York Received 7/3/09; revised 9/3/09; accepted 9/4/09; published OnlineFirst 11/24/09. Grant support: NIH grant UL1RR024996 (J.M. Venstrom), CALGB and Alex's Lemonade Foundation (K.C. Hsu), and Robert Steel Foundation and Katie Find a Cure Fund (N.-K.V. Cheung). The costs of publication of this article were defrayed in part by the payment of page charges. This articlemust therefore be herebymarked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Requests for reprints: Katharine C. Hsu, Box 336, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. Phone: 646-8882667; Fax: 646-422-0298; E-mail: [email protected]. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-1720 7330 Clin Cancer Res 2009;15(23) December 1, 2009 www.aacrjournals.org Research. on May 3, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst November 24, 2009; DOI: 10.1158/1078-0432.CCR-09-1720