The immune landscape of solid pediatric tumors
Background: Large immunogenomic analyses have demonstrated the prognostic role of the functional orientation of the tumor microenvironment in adult solid tumors, this variable has been poorly explored in the pediatric counterpart.
Methods: We performed a systematic analysis of public RNAseq data (TARGET) for five pediatric tumor types (408 patients): Wilms tumor (WLM), neuroblastoma (NBL), osteosarcoma (OS), clear cell sarcoma of the kidney (CCSK) and rhabdoid tumor of the kidney (RT). We assessed the performance of the Immunologic Constant of Rejection (ICR), which captures an active Th1/cytotoxic response. We also performed gene set enrichment analysis (ssGSEA) and clustered more than 100 well characterized immune traits to define immune subtypes and compared their outcome.
Results: A higher ICR score was associated with better survival in OS and high risk NBL without MYCN amplification but with poorer survival in WLM. Clustering of immune traits revealed the same five principal modules previously described in adult tumors (TCGA). These modules divided pediatric patients into six immune subtypes (S1-S6) with distinct survival outcomes. The S2 cluster showed the best overall survival, characterized by low enrichment of the wound healing signature, high Th1, and low Th2 infiltration, while the reverse was observed in S4. Upregulation of the WNT/Beta-catenin pathway was associated with unfavorable outcomes and decreased T-cell infiltration in OS.
Conclusions: We demonstrated that extracranial pediatric tumors could be classified according to their immune disposition, unveiling similarities with adults' tumors. Immunological parameters might be explored to refine diagnostic and prognostic biomarkers and to identify potential immune-responsive tumors.
Shimaa Sherif
Jessica Roelands
William Mifsud
Eiman I Ahmed
Christophe M Raynaud
Darawan Rinchai
Abbirami Sathappan
Ata Maaz
Ayman Saleh
Erdener Ozer
Khalid A Fakhro
Borbala Mifsud
Vésteinn Thorsson
Davide Bedognetti
Wouter R L Hendrickx
J Exp Clin Cancer Res
. 2022 Jun 11;41(1):199. doi: 10.1186/s13046-022-02397-z.
2022
English
Inhibition of phosphorylation of TrkB and TrkC and their signal transduction by alpha2-macroglobulin.
Humans; Animals; Mice; Signal Transduction/drug effects/*physiology; Phosphorylation; Mitogen-Activated Protein Kinase 1/metabolism; Antineoplastic Agents/pharmacology; Type C Phospholipases/metabolism; Cell Differentiation/drug effects; Neuroprotective Agents/*metabolism; Neuroblastoma; alpha-Macroglobulins/*pharmacology; *Mitogen-Activated Protein Kinases; 3T3 Cells/chemistry/cytology/enzymology; Brain-Derived Neurotrophic Factor/pharmacology; Calcium-Calmodulin-Dependent Protein Kinases/metabolism; Isoenzymes/metabolism; Mitogen-Activated Protein Kinase 3; Nerve Growth Factors/pharmacology; Neurotrophin 3; Phospholipase C gamma; Receptor Protein-Tyrosine Kinases/*metabolism; Serotonin/metabolism; Tretinoin/pharmacology; Ciliary Neurotrophic Factor; Receptors; Receptor; Tumor Cells; Cultured/chemistry/cytology/enzymology; Nerve Growth Factor/*metabolism; trkC
Monoamine-activated alpha2-macroglobulin (alpha2M) was shown to reduce the dopamine concentration in corpus striatum of adult rat brains and inhibit other neuronal functions in vivo and in vitro. As brain-derived neurotrophic factor, neurotrophin-4, and neurotrophin-3 are important neurotrophic factors for dopaminergic neurons, the effect of monoamine-activated alpha2M on signal transduction by trkB and trkC was investigated. The results show that monoamine-activated alpha2M binds to trkB and inhibits brain-derived neurotrophic factor/neurotrophin-4-promoted autophosphorylation of trkB in a dose-dependent manner in both trkB-expressing NIH3T3 (NIH3T3-trkB) and human neuroblastoma
Hu Y Q; Koo P H
Journal of neurochemistry
1998
1998-07
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
Prostate apoptosis response-4 enhances secretion of amyloid beta peptide 1-42 in human neuroblastoma IMR-32 cells by a caspase-dependent pathway.
*Intracellular Signaling Peptides and Proteins; Amyloid beta-Peptides/*biosynthesis/metabolism; Apoptosis Regulatory Proteins; Apoptosis/*physiology; Carrier Proteins/genetics/*physiology; Caspases/*metabolism; Cultured; Enzyme Activation; Humans; Kinetics; Leucine Zippers; Neuroblastoma; Peptide Fragments/*biosynthesis/metabolism; Recombinant Proteins/metabolism; Time Factors; Transfection; Tumor Cells
Prostate apoptosis response-4 (Par-4) is a leucine zipper protein that promotes neuronal cell death in Alzheimer's disease (AD). Neuronal degeneration in AD may result from extracellular accumulation of amyloid beta peptide (Abeta) 1-42. To examine the effect of Par-4 on Abeta secretion and to reconcile amyloid/apoptosis hypotheses of AD, we generated IMR-32 cell lines that overexpress Par-4 and/or its leucine zipper domain. Overexpression of Par-4 did not significantly affect levels of the endogenously expressed beta amyloid precursor protein but drastically increased the Abeta(1-42)/Abeta(total) ratio in the conditioned media about 6-8 h after trophic factor withdrawal. Time course analysis of caspase activation reveals that Par-4 overexpression exacerbated caspase activation, which is detectable within 2 h after trophic factor withdrawal. Furthermore, inhibition of caspase activity by the broad spectrum caspase inhibitor BD-fmk significantly attenuated the Par-4-induced increase in Abeta 1-42 production. In addition, the effects of Par-4 on secretion of Abeta 1-42 were consistently blocked by co-expression of the leucine zipper domain, indicating that the effect of Par-4 on Abeta secretion may require its interaction with other protein(s). These results suggest that Par-4 increases secretion of Abeta 1-42 largely through a caspase-dependent pathway after apoptotic cascades are initiated.
Guo Q; Xie J; Chang X; Du H
The Journal of biological chemistry
2001
2001-05
Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).
<a href="http://doi.org/10.1074/jbc.M010996200" target="_blank" rel="noreferrer noopener">10.1074/jbc.M010996200</a>