Using a large and homogeneous cohort of NB patients treated with autologous HSCT, we demonstrate a survival advantage in solid tumor patients lacking HLA class I ligands for autologous inhibitory KIR. Autologous HSCT may provide the milieu that promotes activation and expansion of NK cells leading to improved tumor control and survival following HSCT. This enhanced tumor immunity depends upon the immunogenetic background of the patient, such that patients lacking the HLA class I ligand for autologous inhibitory KIR derive the greatest benefit from NK cell reactivity following HSCT. As a complement to current prognostic factors, KIR-HLA immunogenetics may provide useful insight into how innate immunity can be activated against NB in HSCT.
These data support a model of NK cell behavior whereby tolerance to self is circumvented in autologous HSCT, allowing normally hyporesponsive NK cells expressing inhibitory KIR for non-self HLA class I molecules to achieve effector function and heightened eradication of tumor cells. Functional studies in murine CMV infection and human allogeneic HSCT have recently confirmed NK reactivity according to “missing ligand” (9
). The mechanism underlying this plasticity of NK cell tolerance remains obscure, but the inflammatory environment common to both viral infection and HSCT may be critical for breaking tolerance to self (18
). Similar functional studies in the autologous HSCT setting are necessary, but early findings show that non-self-specific NK cells display functional competence following autologous HSCT in NB patients (unpublished data). The finding that patients lacking the HLA-C1 ligand for KIR2DL2/3 had the highest 3-year survival rate is interesting when taken in the context of previous findings in the allogeneic HSCT setting where expression of KIR2DL2/3 is increased in the first 100 days post-HSCT (19
). Similar phenotype-based reconstitution studies are needed in autologous HSCT.
Rapid and early NK cell recovery following autologous HSCT is associated with better PFS in non-Hodgkin’s lymphoma, Hodgkin’s disease, acute myeloid leukemia, multiple myeloma, and metastatic breast cancer (36
), indicating that other malignancies could potentially benefit from this “missing ligand” effect. In a heterogeneous cohort of 16 patients undergoing autologous HSCT for lymphoma and solid tumors, Leung et al demonstrated a survival advantage for recipients with a KIRHLA mismatch (39
), although another study had conflicting results (40
). By restricting the analysis to a specific tumor population with sufficient numbers of patients, we can definitively demonstrate an innate immune effect dictated by inhibitory KIR-HLA interaction. Finally, other inflammatory stimuli or even other mechanisms of NK cell killing, such as ADCC, may play a role, particularly since nearly all patients in this study received antibody therapy. A better understanding of the biologic complexity responsible for the “missing ligand” effect is crucial for further exploiting NK cells in cancer therapy.
As a complement to known factors associated with NB outcome including histology, DNA ploidy, MYCN
gene amplification, and isotretinoin treatment (2
), KIR-HLA immunogenetics may provide useful insight into how innate immunity can be activated against NB in HSCT. In this study, “missing ligand” was more significant than tumor MYCN
gene amplification. Isotretinoin also had a beneficial effect on survival, although isotretinoin treatment depended somewhat on disease status, which could not be completely adjusted for in the Cox regression analysis. Combining KIR-HLA genotyping with other markers of immune responsiveness, such as Fcγ receptor polymorphisms (41
), may ultimately allow clinicians to determine the most effective and least toxic treatment strategy for an individual patient.
There is a critical need for biomarkers for identifying patients likely to respond to hematopoietic stem cell transplantation (HSCT). For children with high-risk neuroblastoma, predicting outcomes following autologous HSCT would allow clinicians to individualize therapy, optimize long-term survival and prevent unnecessary toxicities. In a population of neuroblastoma patients at high-risk for relapse, we demonstrate that KIR and HLA gene polymorphisms governing natural killer cell function influence disease progression and survival for patients treated with autologous HSCT. Combining prognostic markers linked to host innate immunity with markers of intrinsic tumor biology may more accurately model the host-tumor interaction and better predict survival. Our data open new possibilities for risk-stratifying neuroblastoma patients using a unique immune-based genetic algorithm, and may have implications for other tumors treated with autologous HSCT.