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Page 2 of 12 Schaafsma et al. J Cancer Metastasis Treat 2021;7:34 https://dx.doi.org/10.20517/2394-4722.2021.72

Conclusion: In this study, we have provided a comprehensive evaluation of immune cell infiltration in
neuroblastoma using gene expression data. We propose an important role for B cells in the neuroblastoma tumor
microenvironment and suggest that B cells can be used as a prognostic biomarker to predict recurrence-free and
overall survival independently of currently utilized prognostic variables.

Keywords: Neuroblastoma, immune cell infiltration, prognosis, MYCN amplification, B cells

INTRODUCTION
Neuroblastoma is the most common extracranial childhood cancer and accounts for 8%-10% of all
[1]
childhood cancers . It originates from neural crest progenitor cells and can consequently occur anywhere
along the sympathetic nervous system with the most common location being the adrenal glands .
[2,3]
Neuroblastoma can develop sporadically or display autosomal dominant inheritance. The latter occurs most
commonly due to familial mutations in the ALK or PHOX2B genes . The prognosis of neuroblastoma
[4,5]
[6]
patients has improved in recent years . However, the 5-year survival rate of patients with high-risk disease
is still below 50% , highlighting the need for additional therapies.
[2]
[7]
Immunotherapy has recently led to a significant extension of survival rates in several adult cancers .
Although immunotherapy may also hold great promise for pediatric oncology, few clinical trials are
currently being conducted in solid pediatric cancer types. The increased survival of patients with high-risk
neuroblastoma following the success of anti-GD2 therapy exemplifies the potential of immunotherapy in
neuroblastoma . Thorough characterization of the tumor microenvironment (TME) is essential in
[8]
identifying challenges and opportunities for additional immunotherapy use in neuroblastoma.

Due to the limited availability of fresh neuroblastoma tumor material and the practical challenges of in-
depth immune analyses, several studies have recently investigated the composition of the immune cell
infiltrate in neuroblastoma using gene expression datasets [9-12] . These studies have shown that several
immune cell types infiltrate the neuroblastoma TME, including B cells, CD8+ T cells, NK cells, and
macrophages [9-12] . In addition, these studies have also consistently shown that tumors displaying MYCN
amplifications are significantly less immune infiltrated as compared to patients without MYCN
amplifications [9-12] , which is consistent with more traditional immunohistochemistry (IHC) approaches [9,10] .
However, several open questions remain. First, the majority of these studies only used a limited number of
datasets, which potentially challenges external validity. Second, the association between individual immune
cell types and patient prognosis has only been evaluated in a select number of studies for few immune cell
types. Lastly, while the negative relationship between MYCN amplifications and immune infiltration is
clear, the role of additional commonly altered chromosomal alterations in neuroblastoma and immune cell
infiltration is unclear.

In this study, we aimed at providing a comprehensive investigation of immune cell infiltration in
neuroblastoma using a large number of independent gene expression datasets. We evaluated the
relationship between immune cell infiltration and patient prognosis, co-infiltration of immune cells, and the
association between common chromosomal abnormalities and immune cell infiltration. We found a
surprising role for B cell infiltration in both prognostic and co-infiltration analyses. In conclusion, our
findings both confirm previous studies and propose an important role for B cells in the TME of
neuroblastoma.