Abstract
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 3years 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.
Highlights
Neuroblastoma is the most common extracranial solid tumor in childhood [1]
We retrospectively evaluated benefits of immunotherapy during maintenance treatment by comparing outcome between high-risk stage M NB patients treated with anti-GD2 immunotherapy plus retinoic acid (n = 50) and patients treated with retinoic acid-based therapy alone (n = 33) (Table 1)
Analysis of the ordinal regression model showed that the immune landscape between high-risk NB subgroups displays significant differences (Table 2; Fig. 1B). 11q-deleted NB displayed higher absolute proportion of CD8+ T cells, regulatory T cells (Treg), follicular helper T cells (Tfh) cells, cd T cells, M0, M1, and M2 macrophages compared to MYCN-amplified NB and higher resting CD4+ memory T cells and activated NK cells compared to MYCN-amplified NB and others (P < 0.05) (Fig. 1B)
Summary
Neuroblastoma is the most common extracranial solid tumor in childhood [1]. The OS for patients with lowrisk disease is 85–90%. More than half of the children diagnosed with the high-risk subtype will either not respond to current therapies or relapse after treatment, with a postrelapse OS less than 10–20% [2]. Biological factors associated with increased risk for disease progression include chromosomal alterations in 11q, 3p, 1p, and MYCN amplification (MNA) [3]. 11q and MNA are the most frequent (30% and 20%, respectively), and they are considered as stratifying prognostic markers by the International Neuroblastoma Risk Group (INRG) staging system [4]. MNA inversely correlates with 11q deletion [3,5]. MYCN is yet undruggable and the genetic basis for 11q deletion pathogenesis is unclear
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