Combined Effects of Myeloid Cells in the Neuroblastoma Tumor Microenvironment

Abstract

Despite multimodal treatment, survival chances for high-risk neuroblastoma patients remain poor. Immunotherapeutic approaches focusing on the activation and/or modification of host immunity for eliminating tumor cells, such as chimeric antigen receptor (CAR) T cells, are currently in development, however clinical trials have failed to reproduce the preclinical results. The tumor microenvironment is emerging as a major contributor to immune suppression and tumor evasion in solid cancers and thus has to be overcome for therapies relying on a functional immune response. Among the cellular components of the neuroblastoma tumor microenvironment, suppressive myeloid cells have been described as key players in inhibition of antitumor immune responses and have been shown to positively correlate with more aggressive disease, resistance to treatments, and overall poor prognosis. This review article summarizes how neuroblastoma-driven inflammation induces suppressive myeloid cells in the tumor microenvironment and how they in turn sustain the tumor niche through suppressor functions, such as nutrient depletion and generation of oxidative stress. Numerous preclinical studies have suggested a range of drug and cellular therapy approaches to overcome myeloid-derived suppression in neuroblastoma that warrant evaluation in future clinical studies.

The immune cell atlas of human neuroblastoma

“… 14 In addition, the presence of myeloid-derived suppressor cells has been observed in both human and mouse NB tumors and has been associated with poor prognosis. 21 , 22 These insights into the function of immunity in NB have led to the development of anti-GD2 immunotherapy that is given in conjunction with conventional treatment in high-risk NBs. 23 , 24 …”

Generation of anti-GD2 CAR macrophages from human pluripotent stem cells for cancer immunotherapies

“…Neuroblastoma is the most common and difficult-to-treat type of pediatric solid tumor due to its high genetic heterogeneity ( Boeva et al., 2017 ), making identification of “druggable” targets for small-molecule inhibitors difficult and generation of neoantigens for T cell-based immunotherapies ineffective. However, the neuroblastoma tumor microenvironment is enriched with macrophages ( Frosch et al., 2021 ), and recent data indicate that macrophages could be important mediators of antitumor responses against neuroblastoma in the context of anti-GD2 (redirecting against the tumor) and anti-CD47 (blocking phagocytosis inhibitory pathway) dual-antibody therapy ( Theruvath et al., 2022 ). Here, we show that CAR-Ms may provide an alternative antigen-specific cellular treatment for neuroblastoma.…”

Immunotherapy of Neuroblastoma: Facts and Hopes

“…Despite the lack of evidence of an adaptive immune response, there is also ample evidence that neuroblastoma, in common with most human cancers, has immune evasion hardwired into its biology (12) through mechanisms such as downregulation of MHC class-I (17), infiltration by suppressive myeloid cells (13,(18)(19)(20), and production of inhibitory factors such as arginase-2 (21) and TGFb (22). This raises the intriguing possibility that the relative coldness of neuroblastoma may reflect immune evasion as much as a lack of inherent danger, providing some encouragement for immunotherapeutic strategies.…”