Abstract
RNA and DNA sequencing data are traditionally used to discern intrinsic cellular pathways in cancer pathogenesis, their utility for investigating the tumor microenvironment (TME) has not been fully explored. This study explores the use of sequencing data to investigate immunity within the TME. Here, we use immune cell fraction estimation analysis to determine the immune profiles in the microenvironment of neuroblastoma (NB) based on RNA-seq data in the TARGET database. The correlation between immune cell transcripts and prognosis in pediatric NB is also investigated. In silico analysis revealed a strong inverse correlation between MYCN amplification and leukocyte infiltration. This finding was validated by immunohistochemistry analysis in tumor samples. Moreover, the abundance of CD4 T cells strongly associated with better patient survival regardless of MYCN gene amplification, while those of CD8 T cells, NK or B cells do not. Based on characteristic cytokine expression of CD4 subsets in tumors, the Th2 rather than Th1 levels were associated with better prognosis. We found that the in silico analysis of TARGET database reflected tumor immunity and was validated by the immunohistochemical tumor data. Our results reveal the association of MYCN amplification with repressed cellular immunity and the potential prognostic value of infiltrating CD4 T cell transcripts in pediatric NB. This analysis illustrates the potential role of MYCN in NB as a regulator of immune privilege and characterizes the power of in silico analysis for delineating cancer immunology and risk stratification.
Highlights
Neuroblastoma (NB) is among the most common cancers in childhood
In a 1972 study of histologic lymphocytic infiltration in 23 primary NBs, a positive correlation with survival was found in infancy and childhood [7]. It is established in a number of other tumor types that components of immune infiltration into the tumor plays a critical role in cancer prognosis
22 human hematopoietic cell phenotypes were merged into 16 immune cell types as follows: naive and memory B cells were merged into B cells; naïve, memory, resting, and activated CD4 T cells were merged into CD4 T cells; NK cells resting and NK cells activated were merged into NK cells; dendritic cells resting and dendritic cells activated were merged into DC cells; while mast cells resting and mast cell activated were merged into mast cells
Summary
More than 90% of NB are diagnosed prior to 5 years of age, in which the prognosis of NB varies greatly based on risk stratification [1,2,3]. While >90% of patients with intermediate and low-risk tumors survive 5 years or more, only 40–50% of patients with high-risk NB achieve 5-year survival [4]. MYCN Repression of Cellular Immunity in NB is based on genetic alterations, histological findings as well as age of diagnosis among other clinical factors. While MYCN amp lification and unbalanced 11q aberration have emerged as the dominant factors in risk assignment [5], poorly differentiated or undifferentiated ganglioneuroblastoma, and NB without these genetic alterations can show poor prognosis. It is of interest to search for other shared features of high-risk NB identified by either histology or genetic risk profiles
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