Abstract
Simple SummaryNeuroblastoma is a type of childhood solid cancer often characterized by resistance to treatment and with poor prognosis. The tumors contain a mixture of cell types as well as cancer cells, and one of the most common is a type of blood cells called myeloid cells. In this review article we present a summary of what is known about the function of myeloid cells within neuroblastoma tumors.Despite multimodal treatment, survival chances for high-risk neuroblastoma patients remain poor. Immunotherapeutic approaches focusing on the activation and/or modification of host immunity for eliminating tumor cells, such as chimeric antigen receptor (CAR) T cells, are currently in development, however clinical trials have failed to reproduce the preclinical results. The tumor microenvironment is emerging as a major contributor to immune suppression and tumor evasion in solid cancers and thus has to be overcome for therapies relying on a functional immune response. Among the cellular components of the neuroblastoma tumor microenvironment, suppressive myeloid cells have been described as key players in inhibition of antitumor immune responses and have been shown to positively correlate with more aggressive disease, resistance to treatments, and overall poor prognosis. This review article summarizes how neuroblastoma-driven inflammation induces suppressive myeloid cells in the tumor microenvironment and how they in turn sustain the tumor niche through suppressor functions, such as nutrient depletion and generation of oxidative stress. Numerous preclinical studies have suggested a range of drug and cellular therapy approaches to overcome myeloid-derived suppression in neuroblastoma that warrant evaluation in future clinical studies.
Highlights
As one of the more recently introduced treatments in neuroblastoma, immunotherapy targeting tumors via the abundantly expressed tumor-associated antigen disialogangliosideGD2 has shown promising results [1]
One of the reasons neuroblastoma is hard to treat with immunity-based approaches is its inflammatory character, which leads to the formation of a highly immunosuppressive microenvironment consisting of soluble factors, stromal cells, and alternatively activated immune effectors
This is reflected in a 14-gene signature associated with poor prognosis in neuroblastoma, which contains five genes related to myeloid populations and their suppressive mechanisms (CD14, CD33, IL-10, CD16, IL-6 receptor (IL-6R)) [10]
Summary
As one of the more recently introduced treatments in neuroblastoma, immunotherapy targeting tumors via the abundantly expressed tumor-associated antigen disialoganglioside. Studies investigating neuroblastoma in transgenic TH-MYCN mouse models have shown that tumors undergo a transition from early lesions highly infiltrated with lymphocytes to progressively increasing numbers of myeloid populations in advanced tumors [7,8]. This was further confirmed in immunohistochemical analyses of human tumor samples, where neuroblastoma and other pediatric solid tumors were heavily infiltrated with Cluster of differentiation (CD) 68+ myeloid cells [9]. This review will discuss cellular components of the immunosuppressive microenvironment of neuroblastoma, with a focus on TAM- and MDSC-mediated suppression, and how these myeloid populations can be targeted in the immunotherapy of neuroblastoma
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