Clinical Significance of a CD3/CD8-Based Immunoscore in Neuroblastoma Patients Using Digital Pathology

Abstract

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.

CD20highCD138low tumor-infiltrating lymphocytes predominantly related to cytokine‒cytokine receptor interactions are associated with favorable outcomes in neuroblastoma patients

“…The density of positive staining for CD20 and CD138 was digitally quantified as the number of positive cells per square millimeter (mm 2 ), as described in detail in our previous studies [ 5 , 18 ]. Briefly, all pathological slides were scanned at 200x magnification (Pannaromic Scan 150, 3DHistech, Hungary) and autoexamined by digital analysis.…”

“…Therefore, a comprehensive understanding of tumor-infiltrating lymphocytes (TILs) is crucial for overcoming the challenges and opportunities associated with additional immunotherapy against NB. Several studies have shown that TIL subtypes include B and T cells, macrophages, and natural killer (NK) cells [ [5] , [6] , [7] ]. Tumor-infiltrating T cells are known to be involved in antitumor immunity, and cytotoxic CD8 + T cells, which have been widely investigated in cancers, control tumor growth and metastasis [ 8 ].…”

GM‐CSF, G‐CSF or no cytokine therapy with anti‐GD2 immunotherapy for high‐risk neuroblastoma

“…GM‐CSF signaling activates anti‐tumor response of some eosinophils in mice, although this effect has not been specifically observed with neuroblastoma 66–68 . Notably for neuroblastoma tumorigenesis, DC1 induction 48,49 and CD8+ T cell antitumor immunity promotion 50 by GM‐CSF (Table 2) may be especially important because neuroblastoma cells potently inhibit dendritic cell generation, migration and function, 76–78 and a higher risk of progression and death has been correlated to low CD8+ and other T cell numbers in patients with neuroblastoma 79 …”