Immune Escape Mechanisms and Future Prospects for Immunotherapy in Neuroblastoma

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood with 5-year survival rate of 40% in high-risk patients despite intensive therapies. Recently, adoptive cell therapy, particularly chimeric antigen receptor (CAR) T cell therapy, represents a revolutionary treatment for hematological malignancies. However, there are challenges for this therapeutic strategy with solid tumors, as a result of the immunosuppressive nature of the tumor microenvironment (TME). Cancer cells have evolved multiple mechanisms to escape immune recognition or to modulate immune cell function. Several subtypes of immune cells that infiltrate tumors can foster tumor development, harbor immunosuppressive activity, and decrease an efficacy of adoptive cell therapies. Therefore, an understanding of the dual role of the immune system under the influences of the TME has been crucial for the development of effective therapeutic strategies against solid cancers. This review aims to depict key immune players and cellular pathways involved in the dynamic interplay between the TME and the immune system and also to address challenges and prospective development of adoptive T cell transfer for neuroblastoma.

Figure 1

General model of the interactions between immune and cancer cells in the TME. NB cells play a central role in creating an immunosuppressive microenvironment. Hypoxia poses a metabolic challenge to infiltrating immune cells. NB cells also express membrane-bound and secreted immunosuppressive proteins such as IL-10 and TGF-β, which recruit Tregs, MDSCs, and TAMs and promote their suppressive activity, thus inhibiting the antitumor function of effector cells.

Figure 2

Therapeutic strategies to overcome the immunosuppressive TME. Combinatorial therapeutic approaches where CAR T cells directed against TAA are administered simultaneously with stromal targeted therapy represent the future of NB treatment. CAR T cells can be genetically modified to express various kinds of receptors including a chemokine receptor, a dominant negative receptor, or receptor targeted TME components. These can be provided in combination with other types of targeted therapy such as antibodies, small molecule inhibitors, and/or immune checkpoint inhibitors.