Subtype and grade-dependent spatial heterogeneity of T-cell infiltration in pediatric glioma

Abstract

Brain tumors are the leading cause of cancer-related mortality in children and have distinct genomic and molecular features compared with adult glioma. However, the properties of immune cells in these tumors has been vastly understudied compared with their adult counterparts. We combined multiplex immunofluorescence immunohistochemistry coupled with machine learning and single-cell mass cytometry to evaluate T-cells infiltrating pediatric glial tumors. We show that low-grade tumors are characterized by greater T-cell density compared with high-grade glioma (HGG). However, even among low-grade tumors, T-cell infiltration can be highly variable and subtype-dependent, with greater T-cell density in pleomorphic xanthoastrocytoma and ganglioglioma. CD3+ T-cell infiltration correlates inversely with the expression of SOX2, an embryonal stem cell marker commonly expressed by glial tumors. T-cells within both HGG and low-grade glioma (LGG) exhibit phenotypic heterogeneity and tissue-resident memory T-cells consist of distinct subsets of CD103+ and TCF1+ cells that exhibit distinct spatial localization patterns. TCF1+ T-cells are located closer to the vessels while CD103+ resident T-cells reside within the tumor further away from the vasculature. Recurrent tumors are characterized by a decline in CD103+ tumor-infiltrating T-cells. BRAFV600E mutation is immunogenic in children with LGG and may serve as a target for immune therapy. These data provide several novel insights into the subtype-dependent and grade-dependent changes in immune architecture in pediatric gliomas and suggest that harnessing tumor-resident T-cells may be essential to improve immune control in glioma.

The Growing Relevance of Immunoregulation in Pediatric Brain Tumors

“…Immune classification was also correlated with somatic mutations, copy number alterations, and molecular pathways related to tumorigenesis, metabolism, and immune responses [ 61 ]. The finding that LGGs are characterized by greater immune cell infiltration, especially T cells, compared to HGGs are in line with other publications [ 17 ]. However, even among LGG, T cell infiltration was highly variable and subgroup-dependent, with greater T cell density in pleomorphic xanthoastrocytoma (PXA) and ganglioglioma (GG) [ 17 ].…”

“…However, recent efforts have shown that antitumor immune control exists in pediatric brain tumors, e.g., rhabdoid tumors and LGG showed strong T cell infiltration [ 15 , 16 , 17 ]. Moreover, several studies present prognostications of specific immune cell infiltrates on overall survival [ 18 , 19 , 20 , 21 , 22 ] ( Table 1 ).…”

A Systematic Review of PET Textural Analysis and Radiomics in Cancer

“…We believe that more papers focused on tumor characterization and technical factors would be useful in this regard. On the one hand, although heterogeneity itself was proposed as a biomarker in the past [ 346 , 347 ] it has been reported that heterogeneity is related to biological characteristics such as tumor microenvironment [ 348 , 349 ], genetic expression [ 350 ] and, macroscopically, tumor grades or cancer subtypes [ 351 ]; thus, linking radiomic features with particular biological characteristics could provide additional evidence for the field. On the other hand, further work is still needed to evaluate the impact of image acquisition, reconstruction, post-processing and feature calculation [ 352 ].…”

The Past, Present and Future of Flow Cytometry in Central Nervous System Malignancies

“…The deep profiling capabilities of mass cytometry is also elucidated in the potential to profile the phenotype of brain tumor initiating cells in the context of GBM [ 76 ], while the combination of MC with RNA-seq has allowed the mapping of cellular states of microglia, providing valuable information in the context of how gliomagenesis may occur [ 77 ]. Recent applications of MC have contributed towards the role of the microenviroment in CNSM homeostasis as well as towards the development of immunosuppressive phenotypes, which are distinct depending on the tumor type [ 78 , 79 , 80 , 81 , 82 ].…”