Pediatric Brain Tumours: Lessons from the Immune Microenvironment

Abstract

In spite of recent advances in tumour molecular subtyping, pediatric brain tumours (PBTs) remain the leading cause of cancer-related deaths in children. While some PBTs are treatable with favourable outcomes, recurrent and metastatic disease for certain types of PBTs remains challenging and is often fatal. Tumour immunotherapy has emerged as a hopeful avenue for the treatment of childhood tumours, and recent immunotherapy efforts have been directed towards PBTs. This strategy has the potential to combat otherwise incurable PBTs, while minimizing off-target effects and long-term sequelae. As the infiltration and activation states of immune cells, including tumour-infiltrating lymphocytes and tumour-associated macrophages, are key to shaping responses towards immunotherapy, this review explores the immune landscape of the developing brain and discusses the tumour immune microenvironments of common PBTs, with hopes of conferring insights that may inform future treatment design.

OV Modulators of the Paediatric Brain TIME: Current Status, Combination Strategies, Limitations and Future Directions

“…All PBTs were considered highly immunologically 'cold' in the past, with new insights demonstrating that each entity of a PBT is characterised by a varying immunophenotype that results in heterogenous tumour microenvironments (TME) (Figure 1) [12]. More investigations associated the TIME heterogeneity as a predictor of prognosis and survival [21].…”

“…A suppressive or 'cold' TIME consists of low expression of immunogenic markers on the tumour cells, low infiltration of proinflammatory lymphocytes, an abundance of regulatory immune cells, and the presence of tumour-associated macrophages/microglia (TAM) that hamper effective immunotherapeutic strategies [3,12]. Provided that an immunosuppressive microenvironment in cancer patients correlates with poor prognosis and limits the effectiveness of immunotherapies, strategies to switch from an immunosuppressive to proinflammatory microenvironment may be key for robust and long-term anti-tumour responses required for therapeutic success [13].…”

Non-cellular immunotherapies in pediatric central nervous system tumors

“…The junctions of the pediatric BBB are tighter and are known to be developed by the time an infant is born ( 14 ). Additionally, despite being immunologically naïve, the young infant CNS is entirely capable of mounting a robust immune response ( 15 ), In contrast, age-related stresses and inflammation affect the function and structure of the aged CNS. Additionally, older adults have stiffer, more permeable vasculature in general ( 15 , 16 ).…”

“…Additionally, despite being immunologically naïve, the young infant CNS is entirely capable of mounting a robust immune response ( 15 ), In contrast, age-related stresses and inflammation affect the function and structure of the aged CNS. Additionally, older adults have stiffer, more permeable vasculature in general ( 15 , 16 ). Furthermore, the expression of transmembrane transport proteins varies in pediatric tissue studies when compared to adult ( 17 ).…”

Recent Advances in the Diagnosis and Treatment of Brain Tumors

“…However, surgery, even along with current chemoradiotherapy, is often non-curative for the most aggressive tumors such as high-grade gliomas, medulloblastoma, ATRT and many others [ 12 , 13 ]. As a result, many brain tumor survivors experience serious side effects and long-term sequelae, such as permanent neurological deficits, seizures, and learning disabilities [ 5 , 14 , 15 , 16 ]. To face these challenges, new promising targeted therapies [ 17 , 18 , 19 , 20 ], advanced diagnostic modalities and novel outcome predictors [ 21 , 22 , 23 , 24 , 25 , 26 ] are rapidly emerging in the current literature.…”