Project description:SNP arrays were combined with next generation sequencing (NGS) to precisely define the deleted region in 17 primary 11q-loss neuroblastomas and identify allelic variants in genes relevant for neuroblastoma aetiology. We assessed PARP inhibitor olaparib in combination with other chemotherapy medications using both in vitro and in vivo models.
Project description:SNP arrays were combined with next generation sequencing (NGS) to precisely define the deleted region in 17 primary 11q-loss neuroblastomas and identify allelic variants in genes relevant for neuroblastoma aetiology. We assessed PARP inhibitor olaparib in combination with other chemotherapy medications using both in vitro and in vivo models.
Project description:High-risk neuroblastoma (NB) patients with 11q deletion frequently undergo late but consecutive relapse cycles with fatal outcome. To date, no actionable targets to improve current multimodal treatment have been identified. We analyzed immune microenvironment and genetic profiles of high-risk NB correlating with 11q immune status. We show in two independent cohorts that 11q-deleted NB exhibits various immune inhibitory mechanisms, including increased CD4+ resting T cells and M2 macrophages, higher expression of programmed death-ligand 1, interleukin-10, transforming growth factor-beta-1, and indoleamine 2,3-dioxygenase 1 (P < 0.05), and also higher chromosomal breakages (P ≤ 0.02) and hemizygosity of immunosuppressive miRNAs than MYCN-amplified and other 11q-nondeleted high-risk NB. We also analyzed benefits of maintenance treatment in 83 high-risk stage M NB patients focusing on 11q status, either with standard anti-GD2 immunotherapy (n = 50) or previous retinoic acid-based therapy alone (n = 33). Immunotherapy associated with higher EFS (50 vs. 30, P = 0.028) and OS (72 vs. 52, P = 0.047) at 3 years in the overall population. Despite benefits from standard anti-GD2 immunotherapy in high-risk NB patients, those with 11q deletion still face poor outcome. This NB subgroup displays intratumoral immune suppression profiles, revealing a potential therapeutic strategy with combination immunotherapy to circumvent this immune checkpoint blockade.