Plasma Levels of Soluble HLA-E and HLA-F at Diagnosis May Predict Overall Survival of Neuroblastoma Patients

Abstract

The purpose of this study was to identify the plasma/serum biomarkers that are able to predict overall survival (OS) of neuroblastoma (NB) patients. Concentration of soluble (s) biomarkers was evaluated in plasma (sHLA-E, sHLA-F, chromogranin, and B7H3) or serum (calprotectin) samples from NB patients or healthy children. The levels of biomarkers that were significantly higher in NB patients were then analyzed considering localized or metastatic subsets. Finally, biomarkers that were significantly different in these two subsets were correlated with patient's outcome. With the exception of B7H3, levels of all molecules were significantly higher in NB patients than those in controls. However, only chromogranin, sHLA-E, and sHLA-F levels were different between patients with metastatic and localized tumors. sHLA-E and -F levels correlated with each other but not chromogranin. Chromogranin levels correlated with different event-free survival (EFS), whereas sHLA-E and -F levels also correlated with different OS. Association with OS was also detected considering only patients with metastatic disease. In conclusion, low levels of sHLA-E and -F significantly associated with worse EFS/OS in the whole cohort of NB patients and in patients with metastatic NB. Thus, these molecules deserve to be tested in prospective studies to evaluate their predictive power for high-risk NB patients.

Involvement of IL-10 and TGF-β in HLA-E-mediated neuroblastoma migration and invasion

“…However, that study did not determine whether sHLA-E is released by tumor cells or the immune cells involved in anti-tumor immunity [20]. Our study seemed to have the opposite result.…”

Calprotectin: Clinical Applications in Pediatrics

“…Other investigations have been reported in the literature evaluating calprotectin concentrations in patients with appendicitis, 94,95 congestive heart failure, 96 and others. [97][98][99][100][101] Results did not show significant clinical impact other than increased levels compared to control groups. We speculate that part of the reason why some of these studies have not shown greater merit or have not been followed up with additional investigations is that there has not been the same degree of development, in terms of performance of analytical kits, for serum/plasma and/or urine samples compared to fecal specimens.…”

Immunobiology of HLA Class-Ib Molecules in Transplantation

“…Like HLA-Ia, HLA-E occurs on the surface of cells as a trimolecular complex comprised of HLA-E heavy chain, β2-microglobulin (β2m) and a peptide. In addition, HLA-E can be released into the microenvironment of the allograft and in circulation as soluble HLA (sHLA)-E [32,33]. In contrast to HLA-Ia, HLA-E binds to a restricted set of peptides, commonly derived from the leader sequence of HLA-Ia and HLA-G molecules [34][35][36]; it can also bind to viral, bacterial and stress protein-derived peptides [15,19,37].…”

“…Although HLA-F associates with β2m [48], no information is available on peptide presentation. It is thought to be biologically similar to other HLAIb molecules, such as in pregnancy [29,30] and cancer [32,49]; HLA-F also occurs in circulation as sHLA-F [32] like other sHLA-I molecules. However, the exact function of HLA-F remains to be elucidated.…”

“…This leads to variable levels of protein expression [19,43,45,[62][63][64]. On the other hand, HLA-F is expressed on the cell surface of lymphocytes only upon activation [52] and can be released into the circulation in a soluble form [32]; however, there is not yet any evidence of the effect of specific genotypes of HLA-F or the level of cell-surface expression. The role of HLA-F in histocompatibility remains to be evaluated.…”