Classification of pediatric gliomas based on immunological profiling: Implications for immunotherapy strategies

Abstract

Pediatric gliomas (PGs) are the most common brain tumors in children and the leading cause of childhood cancer-related death. The understanding of the immune microenvironment is essential for developing effective antitumor immunotherapies. Transcriptomic data from 495 PGs were analyzed in this study, with 384 as a training cohort and 111 as a validation cohort. Macrophages were the most common immune infiltrates in the PG microenvironment, followed by T cells. PGs were classified into 3 immune subtypes (ISs) based on immunological profiling: “immune hot” (IS-I), “immune altered” (IS-II), and “immune cold” (IS-III). IS-I tumors, characterized by substantial immune infiltration and high immune checkpoint molecule (ICM) expression, had a favorable prognosis and were more likely to respond to anti-PD1 and anti-CTLA4 immunotherapies, whereas IS-III tumors, characterized by weak immune infiltration and low ICM expression, had a dismal prognosis and poor immunotherapy responsiveness. IS-II tumors represented a transitional stage. Immune classification was also correlated with somatic mutations, copy number alterations, and molecular pathways related to tumorigenesis, metabolism, and immune responses. Three predictive classifiers using eight representative genes were generated by machine learning methods for immune classification. This study established a reliable immunological profile-based classification system for PGs, providing implications for further immunotherapy strategies.

CAR T Cell Therapy’s Potential for Pediatric Brain Tumors

“…The application and integration of these multiplex techniques have been, however, limited in pediatric neuro-oncology, mostly because of the relatively small disease population. Overall, current research indicates that most PBTs trend toward an "immune cold" TME, with a low mutational burden, low T cell infiltration, and high myeloid signatures [85,86].…”

“…The "immune hot" subtype, having the highest fractions of tumor-infiltrating immune cells, is followed by an intermediate inflamed "immune altered" subtype and, lastly, an "immune cold" tumor subtype, which features the lowest tumor-infiltrating T cell fraction. "Immune hot" glial tumors express the highest levels of PD-L1 [85]. Notably, infused CAR T cells express PD-1 and, therefore, are susceptible to PD-L1-mediated suppression [87].…”

Facing CAR T Cell Challenges on the Deadliest Paediatric Brain Tumours

“…Comparing with myeloid cells, the presence of T cells in the TME is low, thus contributing to T cell exhaustion and lack of T cell persistence. Besides, the immunosuppressive cytokines released by TAMs lead to T cell senescence [74] Immune checkpoint inhibitors have emerged as a promising therapy to unblock antitumour T cell responses but have led to some disappointing results in early phase clinical trials for paediatric tumours [4,43,53]. Programmed death ligand 1 (PD-L1) expression in paediatric tumours has been low in general, ranging from 0 to 36% PDL-1 positivity, depending on tumour type.…”

“…pHGGs present with extensive tumour heterogeneity. Although different pHGG subgroups have been proposed in terms of anatomical location, clinical outcome, histone mutations, or pathway alterations, their great heterogeneity complicates their classification and treatment [ 8 , 43 , 44 , 45 , 46 ]. In addition, the molecular genetics of pHGGs differ between infant and older children with HGG [ 47 , 48 ].…”

“…Immune checkpoint inhibitors have emerged as a promising therapy to unblock antitumour T cell responses but have led to some disappointing results in early phase clinical trials for paediatric tumours [ 4 , 43 , 53 ]. Programmed death ligand 1 (PD-L1) expression in paediatric tumours has been low in general, ranging from 0 to 36% PDL-1 positivity, depending on tumour type.…”