High Expression of CCL2 Correlated With Dendritic Cell Recruitment in Neuroblastomas Associated With...

Neuroblastoma (NB) accounts for 10% to 15% of cancer-related deaths among children. In rare cases, NB is associated with opsoclonus-myoclonus syndrome (OMS), a neurological paraneoplastic syndrome. These low-risk (LR) NBs with OMS have a favorable prognosis and an immune-enriched microenvironment. The recruitment of dendritic cells (DCs) and T lymphocytes into tumors is known to be mediated by CCL2 and CXCL12, respectively. We investigated whether intratumor CCL2 and CXCL12 promote DC recruitment within the microenvironment of OMS-associated LR-NBs. We conducted a multicentric retrospective case-control study on 44 pediatric patients with NBs associated or not with OMS. The non-OMS population was subdivided into an LR-NB group versus a high-risk (HR)-NB group, with or without MYCN amplification. Immunohistochemistry was performed using anti-CCL2 and anti-CXCL12 antibodies. DC subpopulations were stained using OPAL spectral multiplex immunofluorescence. Immunostaining scores were established by semiquantitative optical analysis. Gene signatures of DC, as well as CCL2 and CXCL12 mRNA expressions, were also analyzed on a public RNA-Seq data set of NB. We observed a significantly higher protein expression of CCL2 in OMS-associated LR-NBs compared with MYCN-amplified HR-NBs, whereas CXCL12 was not preferentially expressed by any of the NB groups. Furthermore, DC infiltrate was more abundant in OMS-associated LR-NBs compared with any other NB risk groups and positively correlated with CCL2 expression. In silico analysis of public RNA-Seq data demonstrated a higher CCL2 expression in LR-NB with or without OMS compared with HR groups, and that the DC transcriptomic signature was higher in OMS-associated LR-NBs compared with HR-NB groups. We also observed a positive correlation between the DC gene signature and CCL2 or CXCL12 mRNA expression, to a lesser extent. Our results suggest that a DC-prone microenvironment might explain the favorable oncologic outcome of OMS-associated LR-NBs. CCL2 could be a therapeutic target to mobilize DCs in HR-NBs or in tumors characterized by a paucity of tumor-infiltrating DCs.