Neuroblastoma: developmental biology, cancer genomics and immunotherapy

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Abstract

Neuroblastoma is a solid tumour that arises from the developing sympathetic nervous system. Over the past decade, our understanding of this disease has advanced tremendously. The future challenge is to apply the knowledge gained to developing risk-based therapies and, ultimately, improving outcome. In this Review we discuss the key discoveries in the developmental biology, molecular genetics and immunology of neuroblastoma, as well as new translational tools for bringing these promising scientific advances into the clinic.

Key Points

  • Neuroblastoma is a heterogeneous disease. Over 60% of neuroblastomas are metastatic, and most are diagnosed after 18 months of age, with a substantial number carrying MYCN amplification or α-thalassaemia/mental retardation syndrome X-linked (ATRX) mutation, and/or anaplastic lymphoma receptor tyrosine kinase (ALK) mutation. The rest have fairly few somatic mutations and are highly curable with either surgery alone or surgery and low-dose chemotherapy. Neural crest cells and neuroblastoma share common pathways and genes, including paired-like homeobox 2b (PHOX2B), MYCN and ALK.

  • A predictive profile of genetic predisposition to neuroblastoma is emerging via genome-wide association and whole-genome sequencing analyses. However, in contrast to adult cancers, there is a general paucity of recurrent somatic mutations in neuroblastoma.

  • The biology of catecholamine transport has been successfully exploited to provide the tumour-specific neurotransmitter analogue meta-iodobenzylguanidine (MIBG) for diagnosis and anti-neuroblastoma therapy. This advance shows how understanding unique tumour physiology can lead to new therapeutics that are not directly related to specific genetic lesions.

  • Chromosomal aberration is common in neuroblastoma; numerical whole-chromosomal gains are typically found in low-risk tumours, whereas segmental chromosomal gains or losses and somatic mutations are associated with high-risk disease.

  • Research on epigenetic regulation and microRNA control may uncover new prognostic markers and therapeutic targets for neuroblastoma.

  • Neuroblastoma can evade T cells and natural killer cells while exploiting inflammatory macrophages to enhance its survival. Monoclonal antibodies, cytokines and multifunctional antibodies could potentially reactivate antitumour activity in these cells.

  • Anti-GD2 antibodies, when combined with granulocyte–macrophage colony-stimulating factor with or without interleukin-2, are one of the most successful and important strategies for the curative approach to neuroblastoma. Both myeloid effectors and natural killer cells and their cell-surface activating or inhibitory receptors have crucial roles in the clinical response.

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Figure 1: Development of the sympathoadrenal lineage of the neural crest.
Figure 2: ALK and ATRX mutations in neuroblastoma.
Figure 3: Immunotherapy of neuroblastoma.

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Acknowledgements

The authors thank I. Cheung and B. Kushner for their critical review of this manuscript. This work was supported in part by grants from the US National Cancer Institute (NCI) and US Department of Defense (DOD) (NCI-CA161978, DOD-PR111043 and NCI-CA154754 (to N.K.C.)), as well as grants from the US National Institutes of Health (NIH) and NCI (NCI-CA21765, NIH-EY014867, NIH-EY018599 and NCI-CA168875), and funding from the American Lebanese Syrian Associated Charities and the Howard Hughes Medical Institute Early Career Scientist Award (to M.A.D.).

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Correspondence to Nai-Kong V. Cheung or Michael A. Dyer.

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Competing interests

Memorial Sloan-Kettering Cancer Center (MSKCC) has a patent application on hu3F8 and N.K.C. was named as one of the inventors. MSKCC has licensed the patent on β-glucan to Biotec Pharmacon, and the patent on antibody 8H9 to United Therapeutics, and N.K.C. was named as one of the inventors for both agents.

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Glossary

GD2

A disialoganglioside expressed on tumours of neuroectodermal origin, including human neuroblastoma, melanoma, small-cell lung cancer and many sarcomas, with highly restricted expression on normal tissues (such as the cerebellum and peripheral nerves). Two monoclonal antibody families specific for the oligosaccharide epitope of GD2 have been tested extensively in patients, namely the mouse immunoglobulin G3 (IgG3) antibody 3F8 and its humanized version (hu3F8), and the mouse IgG2a antibody 14G2a and its chimeric (ch14.18) or humanized (hu14.18) forms.

Myeloablative

Bone marrow ablation owing to the loss of haematopoietic stem cells following high-dose radiation or chemotherapy.

Adrenal gland

Endocrine organ responsible for generating stress hormones, aldosterone and androgens.

Sympathetic ganglia

Masses of nerve cells that are part of a network controlling autonomic 'fight-or-flight' responses.

Congenital central hypoventilation syndrome

(CCHS). A congenital brain stem disease in which autonomic control of breathing is defective, resulting in sleep apnoea.

Hirschsprung disease

(HSCR). A congenital disease in which the large intestine lacks innervation.

Chromaffin cells

Neuroendocrine cells in the adrenal medulla that receive sympathetic input and release catecholamine neurotransmitters to the systemic circulation.

Event-free survival

A measure of time spent alive without a life-threatening adverse event.

Alternative lengthening of telomeres

(ALT). A recombination-based mechanism that allows telomere length maintenance in the absence of telomerase activity.

Schwannian stromal content

Glial cells in the surrounding stroma, interspersed with neuroblastoma cells. Tumours that are highly differentiated usually have a high Schwannian stromal content.

Mitotic-karyorrhexis index

A measure of the frequency of cells in mitosis with karyorrhexis (nuclear fragmentation associated with cell death).

Hyperdiploidy

Having more than the diploid number of chromosomes, where the DNA index is >1.15.

Complement decay accelerating factor

(CD55). A 70 kDa membrane protein that prevents the assembly of the C3bBb complex (C3-convertase of the alternative pathway of complement activation), thereby blocking formation of the membrane attack complex (MAC).

Protectin

(CD59). A membrane protein that inhibits the membrane attack complex (MAC) by binding C5b678 and preventing C9 from binding and polymerizing.

Complement-mediated cytotoxicity

(CMC). Lysis of a cell resulting from triggering of the complement cascade, in which the binding of an immunoglobulin M (IgM) or IgG antibody to the cell surface is followed by the binding of complement proteins to that antibody.

NK cell-mediated antibody-dependent cell-mediated cytotoxicity

(NK-ADCC). Killing of tumour cells by natural killer cells, the Fc receptor of which adheres to the antibody already attached to the target cell.

Granulocyte ADCC

Killing of tumour cells by granulocytes, the Fc receptor of which adheres to the antibody already attached to the target cell.

Killer cell immunoglobulin-like receptors

(KIRs). Highly polymorphic natural killer cell surface proteins that interact with major histocompatibility complex class I molecules. Most KIRs mediate natural killer cell inhibition instead of activation.

β-glucan

Polysaccharides of D-glucose monomers linked by β-glycosidic bonds. β-glucan (1,3/1,4 linkages) from cereals such as barley or β-glucan (1,3/1,6 linkages) from mushroom and yeasts bind to the dectin 1 receptor and complement receptor 3 (CR3 or CD11b/CD18) and enhance receptor-mediated antitumour properties.

Regulatory T cells

(TReg cells). A T cell subtype that releases suppressive cytokines and silences immune responses.

Anti-idiotype

An antibody binding specifically to an epitope in the variable region of another antibody; when the epitope is the actual antigen-binding site, an anti-idiotypic antibody can mimic the de novo antigen.

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