Targeting the myeloid microenvironment in neuroblastoma

(2023) 42:337 Stip et al. J Exp Clin Cancer Res https://doi.org/10.1186/s13046-023-02913-9 Journal of Experimental & Clinical Cancer Research Open Access REVIEW Targeting the myeloid microenvironment in neuroblastoma Marjolein C. Stip1, Loes Teeuwen1, Miranda P. Dierselhuis2, Jeanette H. W. Leusen1 and Daniëlle Krijgsman1,3*    Abstract Myeloid cells (granulocytes and monocytes/macrophages) play an important role in neuroblastoma. By inducing a complex immunosuppressive network, myeloid cells pose a challenge for the adaptive immune system to eliminate tumor cells, especially in high-risk neuroblastoma. This review first summarizes the pro- and anti-tumorigenic functions of myeloid cells, including granulocytes, monocytes, macrophages, and myeloid-derived suppressor cells (MDSC) during the development and progression of neuroblastoma. Secondly, we discuss how myeloid cells are engaged in the current treatment regimen and explore novel strategies to target these cells in neuroblastoma. These strategies include: (1) engaging myeloid cells as effector cells, (2) ablating myeloid cells or blocking the recruitment of myeloid cells to the tumor microenvironment and (3) reprogramming myeloid cells. Here we describe that despite their immunosuppressive traits, tumor-associated myeloid cells can still be engaged as effector cells, which is clear in anti-GD2 immunotherapy. However, their full potential is not yet reached, and myeloid cell engagement can be enhanced, for example by targeting the CD47/SIRPα axis. Though depletion of myeloid cells or blocking myeloid cell infiltration has been proven effective, this strategy also depletes possible effector cells for immunotherapy from the tumor microenvironment. Therefore, reprogramming of suppressive myeloid cells might be the optimal strategy, which reverses immunosuppressive traits, preserves myeloid cells as effectors of immunotherapy, and subsequently reactivates tumor-infiltrating T cells. Keywords Neuroblastoma, Myeloid cells, Macrophages, Monocytes, Neutrophils, Myeloid-derived suppressor cell, Immunotherapy, Immunosuppression Introduction Neuroblastoma is a pediatric tumor originating from sympathoadrenal lineage dysregulation [1] which exhibits high heterogeneity in disease severity. While low- and intermediate-risk neuroblastoma patients achieve a 80–95% 5-year overall survival rate, high-risk *Correspondence: Daniëlle Krijgsman 1 Center for Translational Immunology, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands 2 Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands 3 Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, the Netherlands cases only reach 45% [2]. Approximately half of the diagnosed neuroblastoma cases are classified as highrisk, with 20–30% featuring MYCN amplification [3]. MYCN, a proto-oncogenic transcription factor, fosters tumor cell proliferation, angiogenesis, and metastasis, concurrently suppressing immune activation [4]. In low-risk cases, no treatment or solely surgery is often curative [5, 6], while high-risk patients undergo induction chemotherapy, surgery, high-dose chemotherapy with autologous stem cell transplantation (ASCT), and radiation therapy [7]. Since 2015, anti-disialoganglioside (GD2) antibody immunotherapy and 13-cis retinoic acid (isotretinoin) is applied as consolidation therapy. Initially anti-GD2 was combined with IL-2 and Granulocyte/Macrophage-Colony Stimulating © The Author(s) 2023. 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The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Stip et al. J Exp Clin Cancer Res (2023) 42:337 Factor (GM-CSF) (USA) or IL-2 only (Europe). Since the administration of IL-2 has been proven to be of no additional benefit this has been omitted [8]. Neuroblastoma has a low mutational burden [9] as well as low human leukocyte antigen (HLA) type I expression [10], limiting tumor recognition by the T cells. Due to the scarcity of neo-antigens, the development of immunotherapeutics, including anti-tumor antibodies, T cell vaccines and chimeric antigen receptor (CAR) T cells hampered initially. However, success was achieved by targeting the highly expressed GD2 [11] using antibody therapy, thereby activating NK cells and myeloid cells. Anti-GD2 antibody therapy significantly improved survival for high-risk neuroblastoma patients [12, 13]. Although GD2-targeting CAR T cells have been developed, they failed to enhance survival initially, likely due to T cell exhaustion by the immunosuppressive tumor microenvironment (TME) (reviewed in [13]). However, recently, a phase I/II trial showed that the use of GD2-targeting CAR T cells (GD2CART01) was feasible and safe in treating high-risk neuroblastoma, resulting in 3-year overall survival and event-free survival of 60% and 36%, respectively [14]. Neuroblastomas, like many solid tumors, harbor a complex immunosuppressive microenvironment hindering immune-mediated tumor clearance. Tumorinfiltrating lymphocytes are often inactivated or exhausted due to immunosuppressive factors, including cytokines (IL-6, IL-10, TGF-β, galectin-1) secreted by tumor, stromal, and myeloid immune cells [15–19]. Furthermore, MYCN overexpression in neuroblastoma cells diminishes NKG2D ligands, impeding NK cell activation [20]. Gangliosides like GD2 (cell-bound or soluble) suppress immunity by binding to myeloid checkpoint Siglec-7 [21], and C D8+ T cell cytotoxicity is curtailed via intracellular granule interference [22]. Lymphocyte activation is further hampered by recruitment and induction of immunosuppressive cells, such as regulatory T cells (Tregs), tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) [23]. While often implicated in immunosuppression, myeloid cell subsets also possess potent anti-tumorigenic properties. This review comprehensively outlines the dualistic roles of myeloid cells in neuroblastoma. The first part summarizes their pro- and anti-tumorigenic (...truncated)