Neuroblastoma Interaction with the Tumour Microenvironment and Its Implications for Treatment and Disease Progression.

Review Neuroblastoma Interaction with the Tumour Microenvironment and Its Implications for Treatment and Disease Progression Leila Jahangiri 1,2 1 2 School of Science and Technology, Nottingham Trent University, Clifton Site, Nottingham NG11 8NS, UK; Division of Cellular and Molecular Pathology, Addenbrookes Hospital, University of Cambridge, Cambridge CB2 0QQ, UK Abstract: Neuroblastoma, a paediatric malignancy of the peripheral nervous system, displays a wide range of clinical outcomes, including regression to fatality despite extensive treatment. Neuroblastoma tumours display a complex interplay with their surrounding environment, known as the tumour microenvironment, which may affect disease progression and patient prognosis. This study aimed to dissect the ways in which neuroblastoma biology, treatment, prognosis, progression, and relapse are linked with the extracellular matrix, the dichotomous identities of neuroblastoma, various regulatory proteins and RNA, and extracellular vesicles within the backdrop of the tumour microenvironment. In addition, other aspects, such as immune cell infiltration, therapeutic options including monoclonal antibodies and small molecule inhibitors; and the ways in which these may affect disease progression and immunosuppression within the context of the neuroblastoma tumour microenvironment, are addressed. Such studies may shed light on useful therapeutic targets within the tumour microenvironment that may benefit groups of NB patients. Ultimately, a detailed understanding of these aspects will enable the neuroblastoma scientific community to improve treatment options, patient outcomes, and quality of life. Keywords: neuroblastoma; tumour microenvironment; disease progression; treatment Citation: Jahangiri, L. Neuroblastoma Interaction with the Tumour Microenvironment and Its Implications for Treatment and Disease Progression. Curr. Oncol. 2023, 30, 9116–9140. https://doi.org/ 10.3390/curroncol30100659 Received: 17 August 2023 Revised: 24 September 2023 Accepted: 12 October 2023 Published: 15 October 2023 Copyright: © 2023 by the author. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1. Introduction to NB and the Tumour Microenvironment Neuroblastoma (NB) is a rare heterogeneous paediatric tumour that, despite only accounting for circa 10% of cancer diagnoses in children, disproportionately leads to 15% of cancer-related deaths in this age group [1,2]. Circa 1200 new cases of NB are diagnosed per annum in the United States and Europe [1,3]. Further, NB is a cancer of the sympathetic nervous system presenting in the abdominal cavity, specifically in the adrenal glands and sympathetic ganglia along paravertebral sympathetic chains [4]. These sympathetic chains and suprarenal ganglia originate from the neural crest cells [5], while single-cell sequencing suggests that neural crest-like Schwann cell precursors (SCPs) give rise to sympathoblasts, which in turn transition to chromaffin cells [6]. Due to the neuroendocrine nature of NB cells, they secrete catecholamines, which may activate β-adrenergic receptors [7]. The staging of NB was initially developed by the International Neuroblastoma Staging System (INSS) based on the propensity for surgical removal of the tumour; therefore, stages 1 and 2 encompassed localised tumours with complete and incomplete gross excision potential, respectively [8]. Stage 3 represented the unilateral presence of a tumour across the midline in the absence or presence of lymph node involvement, and stage 4 represented any primary tumour with dissemination to distant tissue. Finally, 4S represented localised primary tumours limited to bone marrow (not cortical bone), liver, and skin in patients under the age of 12 months [8]. INSS may not be suitable for pretreatment stratification; hence, the International Neuroblastoma Risk Group (INRG) defined the INRG staging system (INRGSS). In this classification system, locoregional tumours are classified as L1 Curr. Oncol. 2023, 30, 9116–9140. https://doi.org/10.3390/curroncol30100659 https://www.mdpi.com/journal/curroncol Curr. Oncol. 2023, 30 9117 and L2 on the grounds of the absence or presence of image-defined risk factors (IDRFs), respectively. IDRFs are specific features within images that are linked to a poor prognosis. Further, metastatic tumours are referred to as M except for those that are metastatic special (MS), in which there is a confinement of metastasis to specific tissues such as the bone marrow (not cortical bone), skin, and liver in patients younger than the age of 18 months [9]. In addition, risk stratification at the time of diagnosis is based on MYCN amplification status (an MYCN copy number increase is strongly linked to poor prognosis), ploidy, stage, age, and segmental chromosomal alteration status (e.g., 11q loss), and it is noteworthy that close to half of all cases of NB are categorised as high-risk and only half of these cases achieve long-term survival [4,9,10]. Many high-risk NB tumours initially respond to treatment inclusive of COJEC (cisplatin, vincristine, carboplatin, etoposide, and cyclophosphamide) within 70 days on 10-day intervals (8 in total), followed by stem cell transplantation, surgery, radiotherapy, isotretinoin, and anti-GD2 antibodies to eliminate any residual disease. Most NB patients display remission; however, relapse may still occur due to the dominance of treatment-resistant clones [11,12]. NBs are highly heterogeneous, which may reflect their divergent molecular and clinical attributes, leading to a variable clinical course and treatment efficacy [11–15]. Cellular and molecular mechanisms, various molecules, and processes of the tumour microenvironment (TME) may contribute to this observed heterogeneity [16]. For example, the TME, which includes the extracellular matrix (ECM), is a highly dynamic network comprising numerous proteoglycans, proteins, and glycoproteins that constantly undergo deposition and degradation, allowing for the instigation and integration of signals that may affect the NB tumour and its biological and clinical attributes [17,18]. Furthermore, the intrinsic properties of NB tumours and their profile of differentially expressed RNA and proteins may contribute to the interaction between NB and the TME [19–21]. The TME also includes stromal and immune cells and a repertoire of secreted molecules, cytokines, and chemokines [15]. Concerning the immune landscape within the TME in NB, recent studies showed the presence of T cells, B cells, natural killer (NK) cells, and myeloid cells such as myeloid-derived suppressor cells (MDSCs) [22]. NB tumours may also differ in their tendency to harbour various types of immune cells, including CD8+ T cells or noninflammatory M2 macrophages [23]. Moreover, extracellular vesic (...truncated)