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Recent advances have revealed that the role of the immune system is prominent in the antitumor response. In the present study, it is aimed to provide an expression profile of tumor-infiltrating lymphocytes (TILs), including mature B cells, plasma cells, and their clinical relevance in neuroblastoma. The expression of CD20 and CD138 was analyzed in the Cangelosi786 dataset (n = 769) as a training dataset and in our cohort (n = 120) as a validation cohort. CD20 high expression was positively associated with favorable overall survival (OS) and event-free survival (EFS) (OS: P

Background Neuroblastoma (NB) places a substantial health burden on families worldwide. This study aimed to develop an immune checkpoint-based signature (ICS) based on the expression of immune checkpoints to better assess patient survival risk and potentially guide patient selection for immunotherapy of NB.Methods Immunohistochemistry integrated with digital pathology was used to determine the expression levels of 9 immune checkpoints in 212 tumor tissues used as the discovery set. The GSE85047 dataset (n=272) was used as a validation set in this study. In the discovery set, the ICS was constructed using a random forest algorithm and confirmed in the validation set to predict overall survival (OS) and event-free survival (EFS). Kaplan-Meier curves with a log-rank test were drawn to compare the survival differences. A receiver operating characteristic (ROC) curve was applied to calculate the area under the curve (AUC).Results Seven immune checkpoints, including PD-L1, B7-H3, IDO1, VISTA, T-cell immunoglobulin and mucin domain containing-3 (TIM-3), inducible costimulatory molecule (ICOS) and costimulatory molecule 40 (OX40), were identified as abnormally expressed in NB in the discovery set. OX40, B7-H3, ICOS and TIM-3 were eventually selected for the ICS model in the discovery set, and 89 patients with high risk had an inferior OS (HR 15.91, 95% CI 8.87 to 28.55, p

Summary: Aberrant minichromosome maintenance (MCM) expression is associated with tumorigenesis. Here, we performed immunohistochemistry integrated with digital pathology to identify MCM2/5/6 expression in 130 neuroblastoma patients. A risk score was established using least absolute shrinkage and selection operator that predicts outcomes according to MCM2 expression, age, and the International Neuroblastoma Staging System in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) dataset (n = 150), where the patients with high risk had significantly worse prognosis that was validated in a hospital-based cohort (n = 130). After multivariable adjustment, the risk model remained an independent factor for survival in the TARGET cohort (overall survival [OS]: hazard ratio [HR] 2.3, 95% confidence interval [CI] 1.4–4.0; event-free survival [EFS]: HR 1.8, 95% CI 1.1–3.1) and for OS in the validation cohort (HR 8.3, 95% CI 1.6–44.5). The ESTIMATE indicates that the risk model is negatively correlated with low ESTIMATE and stromal scores. These findings show the additive nature of this score, fostering its future implementation with new prognostic variables.

Introduction: Metabolic deregulation, a hallmark of cancer, fuels cancer cell growth and metastasis. Phosphoserine phosphatase (PSPH), an enzyme of the serine metabolism pathway, has been shown to affect patients’ prognosis in many cancers but its significance in neuroblastoma remains unknown. Here, we show that the functional role and potential mechanism of PSPH and it is correlated with survival of neuroblastoma patients.Patients and Methods: The TARGET dataset (n = 151) and our hospital-based cases (n = 55) were used for assessing the expression level of PSPH associated with survival in neuroblastoma patients, respectively. Then, in vitro experiments were performed to define the role of PSPH in neuroblastoma. The ESTIMATE and TIMER algorithms were utilized to examine the correlation between PSPH expression level and abundance of immune cells. Further, Kaplan-Meier survival analysis was performed to evaluate the effect of both PSPH and immune cells on patients’ prognosis.Results: High expression of PSPH was significantly associated with unfavorable overall survival (OS) and event-free survival (EFS) in both the TARGET dataset and our hospital-based cases, and was an independent predictor of OS (hazard ratio, 2.00; 95% confidence intervals, 1.21–3.30, p = 0.0067). In vitro experiments showed that high expression of PSPH significantly promoted cell growth and metastasis. Further, the ESTIMATE result suggested that high expression level of PSPH was negatively associated with low stromal and ESTIMATE score. Specifically, high PSPH expression was found to be negatively associated with CD8+ T cell, macrophages and neutrophils, which negatively affected survival of neuroblastoma patients (p < 0.0001, p = 0.0005, and p = 0.0004, respectively).Conclusion: These findings suggested that PSPH expression could be a promising indicator for prognosis and immunotherapy in neuroblastoma patients by potentially influencing infiltration levels of immune cells.

BackgroundInfiltrating immune cells have been reported as prognostic markers in many cancer types. We aimed to evaluate the prognostic role of tumor-infiltrating lymphocytes, namely CD3+ T cells, CD8+ cytotoxic T cells and memory T cells (CD45RO+), in neuroblastoma.Patients and MethodsImmunohistochemistry was used to determine the expression of CD3, CD8 and CD45RO in the tumor samples of 244 neuroblastoma patients. We then used digital pathology to calculate the densities of these markers and derived an immunoscore based on such densities.ResultsDensities of CD3+ and CD8+ T cells in tumor were positively associated with the overall survival (OS) and event-free survival (EFS), whereas density of CD45RO+ T cells in tumor was negatively associated with OS but not EFS. An immunoscore with low density of CD3 and CD8 (CD3-CD8-) was indictive of a greater risk of death (hazard ratio 6.39, 95% confidence interval 3.09-13.20) and any event (i.e., relapse at any site, progressive disease, second malignancy, or death) (hazard ratio 4.65, 95% confidence interval 2.73-7.93). Multivariable analysis revealed that the CD3-CD8- immunoscore was an independent prognostic indicator for OS, even after adjusting for other known prognostic indicators.ConclusionsThe new immunoscore based on digital pathology evaluated densities of tumor-infiltrating CD3+ and CD8+ T cells contributes to the prediction of prognosis in neuroblastoma patients.