Exploring and Targeting the Tumor Immune Microenvironment of Neuroblastoma

Abstract

free survival [10]. Conversely, our group has demonstrated that a subset of high-risk MYCN-not-amplified (MYCN-NA) neuroblastomas have increased T-cell infiltration, suggesting the presence of antigenic targets and an active anti-tumor immune response [11,12]. We further showed in two independent patient cohorts that a high MYCN functional gene expression signature in MYCN-NA tumors is associated with decreased immune infiltrate and a poor overall survival. In this commentary, we review previous studies to interrogate the TME, highlight the diverse TME subtypes of neuroblastoma, and explain why profiling the TME is clinically relevant. We further propose future research directions and therapeutic opportunities informed by studies of the TME to ultimately improve patient outcomes.

Fundamentals and Applications of Focused Ultrasound-Assisted Cancer Immune Checkpoint Inhibition for Solid Tumors

“…HER2 + BC is reported to have a similar phenotype to TNBC [ 167 , 168 ]. The immune phenotypes are determined through TIL infiltration proportions and immune transcriptome profiling in neuroblastoma [ 169 ], glioma [ 170 ], gene expression data from the Cancer Genome Atlas for OC [ 171 ], and TIL infiltration for CRC-MSI [ 46 , 172 ] and HCC [ 173 ]. Acronyms: CRC-MSI: colorectal cancer—microsatellite instable; NSCLC: non-small cell lung cancer; RCC: renal cell carcinoma; HER2 + BC: HER2 + breast cancer; TNBC: triple-negative breast cancer; CRC-MSS: colorectal cancer—microsatellite stable; PDAC: pancreatic ductal adenocarcinoma; NB: neuroblastoma; OC: ovarian cancer; HCC: hepatocellular carcinoma; TMB: tumor mutational burden; T-HIFU: thermal HIFU; M-HIFU: mechanical HIFU; HT: hyperthermia; pFUS: pulsed FUS; UTMC: ultrasound-targeted microbubble cavitation.…”

The Neuroblastoma Microenvironment, Heterogeneity and Immunotherapeutic Approaches

“…The heterogeneity observed in neuroblastoma is also reflected in the immune landscape. Based on risk and MYCN amplification, Masih et al identified distinct clusters depicting low-risk, MYCN-non-amplified high-risk, and MYCN-amplified ultra high-risk neuroblastoma cases [111]. While the ultra high-risk cases showed a generally cold TME, with few tumor-infiltrating lymphocytes (TILs) and downregulation of major histocompatibility complex (MHC) class II, the MYCN-non-amplified high-risk groups were characterized by a hot TME, exhibiting increased infiltration by NK and CD8+ T-cells and expression of immune checkpoint proteins.…”

“…While the ultra high-risk cases showed a generally cold TME, with few tumor-infiltrating lymphocytes (TILs) and downregulation of major histocompatibility complex (MHC) class II, the MYCN-non-amplified high-risk groups were characterized by a hot TME, exhibiting increased infiltration by NK and CD8+ T-cells and expression of immune checkpoint proteins. Additionally, there was a second MYCN-non-amplified high-risk clone with a higher stroma signature and an immunosuppressive TME, characterized by Treg, tumor-associated macrophages (TAMs), and MDSC populations [111].…”

Biological Insight and Recent Advancement in the Treatment of Neuroblastoma

“…The majority of neuroblastoma tumors are immunologically "cold" and devoid of antitumor immune cells and/or they are infiltrated by immune-suppressive cell types, rather than being 'hot" tumors which are infiltrated by effector immune cells, such as the cytotoxic T cells that can kill tumors cells [14]. As a result, it is difficult to develop therapies that target specific immunologic mechanisms [15]. Dysregulated cellular signaling and metabolism within tumor cells would affect the TME and the response to immunotherapy.…”