Targeting the myeloid microenvironment in neuroblastoma

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.

The Neuroblastoma Microenvironment, Heterogeneity and Immunotherapeutic Approaches

“…Similarly to other cancers, neuroblastoma has evolved immune evasion strategies such as downregulation of MHC class-1 expression, increased activity of immune inhibitor factors such as TGFβ and arginase-2, and enhanced infiltration of suppressive myeloid cells [31,[96][97][98]. In neuroblastoma, monocytic (M-MDSC) and polymorphonuclear myeloid-derived suppressor cells (PN-MDSCs) seem to be responsible for suppressing Tcell responses, while M-MDSC are more associated with neuroblastoma tumor progression compared to PN-MDSC [99,100].…”

“…The current knowledge regarding the presence and functions of neutrophils within the TME of neuroblastoma, their interactions with tumor cells, and their prognostic significance is still not understood [100]. Conflicting data have been reported on the correlation between the number of neutrophils and disease progression.…”

“…Mast cells and basophils have not been found to be associated with neuroblastoma; however, eosinophils expressing insulin-like growth factor IGF-2 have been identified in tumors and linked to worse patient survival [100]. The majority of myeloid cells in neuroblastoma tumors are dendritic cells (DCs), monocytes, and macrophages [31,107].…”

“…Dendritic cells have been associated with a better prognosis [108]. In human neuroblastoma, the M2 macrophage phenotype is more common than M1, and M2 has been associated with worse clinical prognosis and metastasis to the bone marrow [100,109,110]. However, others discovered lower M2 levels in high-risk cases [31].…”