Impaired Antitumor Immune Response in -amplified Neuroblastoma Is Associated with Lack of CCL2 Secretion and Poor Dendritic Cell Recruitment.

UNLABELLED

In neuroblastoma, amplification is associated with sparse immune infiltrate and poor prognosis. Dendritic cells (DC) are crucial immune sentinels but their involvement in neuroblastoma pathogenesis is poorly understood. We observed that the migration of monocytes, myeloid and plasmacytoid DC induced by -nonamplified neuroblastoma 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 RNA sequencing and microarray datasets, we describe lower level of expression of in -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 DCs. Among these cells, the CD1c subset may recruit T cells by means of CCL19/CCL22 secretion. , supernatants from DCs cocultured with neuroblastoma 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 neuroblastoma cell lines, and found -nonamplified neuroblastoma cell lines were able to create a microenvironment where DC activation is enhanced. Overall, our findings highlight a major role for CCL2/CCR2 axis in monocytes, myeloid and plasmacytoid cells recruitment toward -nonamplified neuroblastoma, allowing further immune cell recruitment, and show that these tumors present a microenvironment that can favor DC responses.

SIGNIFICANCE

In -nonamplified neuroblastoma, CCL2 produced by neuroblastoma cells induces the recruitment of antigen-presenting cells (DCs and monocytes/macrophages), allowing infiltration by T cells, in link with CCL19 and CCL22 production, hence favoring immune responses.