The immune cell atlas of human neuroblastoma

Verhoeven, Bronte Manouk; Mei, Shenglin; Olsen, Thale Kristin; Gustafsson, Karin; Valind, Anders; Lindström, Axel; Gisselsson, David; Fard, Shahrzad Shirazi; Hagerling, Catharina; Kharchenko, Peter V.; Kogner, Per; Johnsen, John Inge; Baryawno, Ninib

doi:10.1016/j.xcrm.2022.100657

Cited by 33 publications

(46 citation statements)

References 91 publications

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“…To understand whether CCL2 + tumor cells were of mesenchymal tumor cell lineage, we analyzed previously generated single-cell RNA sequencing (scRNA-seq) data from a treated MNA + neuroblastoma tumor ( Figure 3e ). 38 In line with previous work, the majority of CCL2 -expressing tumor cells belonged to the mesenchymal population ( Figure 3f ).…”

Section: Resultssupporting

confidence: 91%

“…The tumor microenvironment in neuroblastoma has been previously investigated, revealing a complex network of interactions between tumor cells and various immune cell populations. 38 However, to our knowledge, no previous study has compared the immune landscape in neuroblastoma tumors before and after treatment. One study did, however, determine immune profiles in the peripheral blood of high-risk neuroblastoma patients before and over the course of treatment, revealing a high degree of interpatient immune variability and the existence of both immune-enhancing and regulatory responses during treatment.…”

Section: Discussionmentioning

confidence: 99%

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Macrophage infiltration promotes regrowth in MYCN-amplified neuroblastoma after chemotherapy

et al. 2023

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Despite aggressive treatment, the 5-year event-free survival rate for children with high-risk neuroblastoma is <50%. While most high-risk neuroblastoma patients initially respond to treatment, often with complete clinical remission, many eventually relapse with therapy-resistant tumors. Novel therapeutic alternatives that prevent the recurrence of therapy-resistant tumors are urgently needed. To understand the adaptation of neuroblastoma under therapy, we analyzed the transcriptomic landscape in 46 clinical tumor samples collected before (PRE) or after (POST) treatment from 22 neuroblastoma patients. RNA sequencing revealed that many of the top-upregulated biological processes in POST MYCN amplified (MNA + ) tumors compared to PRE MNA + tumors were immune-related, and there was a significant increase in numerous genes associated with macrophages. The infiltration of macrophages was corroborated by immunohistochemistry and spatial digital protein profiling. Moreover, POST MNA + tumor cells were more immunogenic compared to PRE MNA + tumor cells. To find support for the macrophage-induced outgrowth of certain subpopulations of immunogenic tumor cells following treatment, we examined the genetic landscape in multiple clinical PRE and POST tumor samples from nine neuroblastoma patients revealing a significant correlation between an increased amount of copy number aberrations (CNA) and macrophage infiltration in POST MNA + tumor samples. Using an in vivo neuroblastoma patient-derived xenograft (PDX) chemotherapy model, we further show that inhibition of macrophage recruitment with anti-CSF1R treatment prevents the regrowth of MNA + tumors following chemotherapy. Taken together, our work supports a therapeutic strategy for fighting the relapse of MNA + neuroblastoma by targeting the immune microenvironment.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Macrophage infiltration promotes regrowth in MYCN-amplified neuroblastoma after chemotherapy

et al. 2023

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“…Our hESC-based model provides a tractable system for analysing tumour initiation events within disease-relevant human embryonic cell-like populations. However, in this study, we focused on cell-intrinsic transcriptional regulation since our cultures lack tumour-relevant, non-NC cell types (e.g., immune cells or Schwann cells) and do not recapitulate the structural and physical properties of the human tumour micro-and macroenvironment [86][87][88][89] . In the future, it will be possible to combine our system with 3D co-culture approaches with defined cell types or to use biomimetic scaffolds to emulate cell-cell interactions and extrinsic environmental influences.…”

Section: Discussionmentioning

confidence: 99%

A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations

Saldana-Guerrero

Montaño-Gutierrez

Hafemeister

et al. 2022

Preprint

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Early childhood tumours are thought to arise from transformed embryonic cells, which often carry large copy number variants (CNVs). However, it remains unclear how CNVs contribute to embryonic tumourigenesis due to a lack of suitable models. Here we employ human embryonic stem cell (hESC) differentiation to assess the effects of chromosome 17q/1q gains, which are prevalent in the embryonal tumour neuroblastoma (NB). We show that CNVs impair the specification of hESC-derived trunk neural crest (NC) cells and their sympathoadrenal derivatives, the putative cells-of-origin of NB. Overexpression of MYCN, whose amplification co-occurs with CNVs in NB, exacerbates the differentiation block, and enables tumourigenic cell proliferation. We find links between disrupted cell states in vitro and tumour cells and connect these states with stepwise disruption of developmental transcription factor networks. Together, our results chart a possible route to NB and provide a mechanistic framework for the CNV-driven initiation of embryonal tumours.

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“…High-risk MYCN-nonamplified NB tumors are often infiltrated by immune cells including tumor-associated monocytes and macrophages. [8][9][10] Moreover, patients with tumors expressing higher levels of an inflammatory gene signature associated with monocytes or macrophages (CD14, CD16, IL-6, IL-6R, and TGFB1) had worse 5-year progression-free survival than patients without this signature, highlighting the role of inflammation in promoting a tumor microenvironment (TME) favorable for NB growth. 9 11 Monocytes and macrophages are major components of the TME in many types of solid tumors.…”

Section: Open Accessmentioning

confidence: 99%

Interaction between tumor cell TNFR2 and monocyte membrane-bound TNF-α triggers tumorigenic inflammation in neuroblastoma

Tomolonis

Dholakia

et al. 2023

J Immunother Cancer

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BackgroundTumor progression and resistance to therapy in children with neuroblastoma (NB), a common childhood cancer, are often associated with infiltration of monocytes and macrophages that produce inflammatory cytokines. However, the mechanism by which tumor-supportive inflammation is initiated and propagated remains unknown. Here, we describe a novel protumorigenic circuit between NB cells and monocytes that is triggered and sustained by tumor necrosis factor alpha (TNF-α).MethodsWe used NB knockouts (KOs) of TNF-α andTNFRSF1AmRNA (TNFR1)/TNFRSF1BmRNA (TNFR2) and TNF-α protease inbitor (TAPI), a drug that modulates TNF-α isoform expression, to assess the role of each component in monocyte-associated protumorigenic inflammation. Additionally, we employed NB-monocyte cocultures and treated these with clinical-grade etanercept, an Fc-TNFR2 fusion protein, to neutralize signaling by both membrane-bound (m) and soluble (s)TNF-α isoforms. Further, we treated NOD/SCID/IL2Rγ(null) mice carrying subcutaneous NB/human monocyte xenografts with etanercept and evaluated the impact on tumor growth and angiogenesis. Gene set enrichment analysis (GSEA) was used to determine whether TNF-α signaling correlates with clinical outcomes in patients with NB.ResultsWe found that NB expression of TNFR2 and monocyte membrane-bound tumor necrosis factor alpha is required for monocyte activation and interleukin (IL)-6 production, while NB TNFR1 and monocyte soluble TNF-α are required for NB nuclear factor kappa B subunit 1 (NF-κB) activation. Treatment of NB-monocyte cocultures with clinical-grade etanercept completely abrogated release of IL-6, granulocyte colony-stimulating factor (G-CSF), IL-1α, and IL-1β and eliminated monocyte-induced enhancement of NB cell proliferation in vitro. Furthermore, etanercept treatment inhibited tumor growth, ablated tumor angiogenesis, and suppressed oncogenic signaling in mice with subcutaneous NB/human monocyte xenografts. Finally, GSEA revealed significant enrichment for TNF-α signaling in patients with NB that relapsed.ConclusionsWe have described a novel mechanism of tumor-promoting inflammation in NB that is strongly associated with patient outcome and could be targeted with therapy.

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The immune cell atlas of human neuroblastoma

Cited by 33 publications

References 91 publications

Macrophage infiltration promotes regrowth in MYCN-amplified neuroblastoma after chemotherapy

Macrophage infiltration promotes regrowth in MYCN-amplified neuroblastoma after chemotherapy

A human neural crest model reveals the developmental impact of neuroblastoma-associated chromosomal aberrations

Interaction between tumor cell TNFR2 and monocyte membrane-bound TNF-α triggers tumorigenic inflammation in neuroblastoma

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