In neuroblastoma (NB), MYCN amplification is associated with sparse immune infiltrate, and poor prognosis. Dendritic cells (DCs) are crucial immune sentinels but their involvement in NB pathogenesis is poorly understood. We observed that the migration of monocytes, MDC and PDC induced by MYCN non-amplified NB supernatants was abrogated by the addition of anti-CCL2 antibodies, demonstrating the involvement of the CCR2/CCL2 axis in their recruitment by these tumors. Using public RNAseq and microarray data sets, we describe lower level of expression of CCL2 in MYCN-amplified neuroblastoma tumors, and we propose a working model for T cell recruitment in neuroblastoma tumors in which CCL2 produced by neuroblastoma cells initiates the recruitment of monocytes, myeloid and plasmacytoid dendritic cells. Among these cells, the CD1C+ subset may recruit T cells by means of CCL19/CCL22 secretion. In vitro, supernatants from dendritic cells co-cultured with NB cell lines and activated contain CCL22 and CCL19, and are chemotactic for both CD4+ and CD8+ T cells. We also looked at immunomodulation induced by NB cell lines, and found MYCN non-amplified NB cell lines were able to create a microenvironment where dendritic cell activation is enhanced. Overall, our findings highlight a major role for CCL2/CCR2 axis in monocytes, myeloid and plasmacytoid cells recruitment towards MYCN non-amplified neuroblastoma, allowing further immune cell recruitment, and show that these tumors present a microenvironment that can favor dendritic cell responses.

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