Subgroup-specific immune and stromal microenvironment in medulloblastoma

Abstract

Knowledge on immune and stromal cells in medulloblastoma microenvironment is still limited as previous work was frequently restricted by low sample size and the lack of molecular subgroup information. We characterized 10 microenvironment cell populations as well as from gene expression in 1422 brain tumors and 763 medulloblastomas. All in all, medulloblastomas showed low expression of immune markers. Still, there were substantial differences with a clustering of medulloblastoma subgroups according to their microenvironment profile. Specifically, SHH medulloblastomas displayed strong signatures of fibroblasts, T cells and macrophages, while markers of cytotoxic lymphocytes were enriched in Group 4 tumors. gene expression appeared to be relatively high in single SHH and WNT cases but was undetectable by immunohistochemistry. In addition, two diverse immuno-stromal patterns were identified, indicating distinct types of local tumor immunosuppression, which were primarily controlled by either macrophage and regulatory T cell-mediated mechanisms or immunosuppressive cytokines and checkpoints, respectively. None of the immune cell signatures had an independent prognostic value in the present dataset after multiple testing correction. These results suggest a mild, but subgroup-specific infiltration of immune cells in medulloblastoma.

Tumor-Specific T Cell Activation in Malignant Brain Tumors

“…Furthermore, correlative analysis of TIL numbers in pediatric medulloblastoma showed no association of an increased lymphocyte infiltration with prolonged survival (14). However, difference in immune infiltration could be observed between different medulloblastoma subtypes, with SHH tumors having the strongest infiltration of T cells (15). The study even described that patients with higher numbers of granzyme B-positive CTLs, i.e., activated CD8 + cells, had a shorter survival compared to patients with low granzyme B-positive CTLs (14).…”

“…In medulloblastoma and other malignant brain tumors, studies on the involvement of T regs in tumor progression are scarce. Gene expression studies found a higher T reg marker expression in the WNT medulloblastoma subtype (15). A recent investigation in medulloblastoma tissue, showed that a tumor driving pathway, e.g., mTOR activation can cross-talk with indolamin-desoxygenase (IDO) expression, which consecutively induces T reg cell expansion and immunosuppression of tumor-specific immune responses (25).…”

Molecular Heterogeneity and Cellular Diversity: Implications for Precision Treatment in Medulloblastoma

“…TME encompasses the various signaling molecules, supporting cells, immune system cells, blood vessels, extracellular matrices, and nutrients that contribute to tumor progression and therapy response [64,65]. Emerging evidence based on preclinical MB models and bioinformatic analyses of clinical MB samples indicates significant TME heterogeneity across different MB subgroups [66][67][68][69].…”

“…Infiltration of various immune cells in TME is of great interest because these infiltrating leukocytes either interfere with tumor progression or promote tumor growth, underlying response and efficacy of immunotherapy. Recent studies based on the quantification of gene expression signatures uncovered dramatical diversity of immune TME among the MB subgroups [68,69]. Of interest, SHH MB, but not Group 3 MB, displays strong signatures of macrophages and T cells, while Group 3 MB is enriched with the highest number of CD8 + T cells; PD-L1 expression is highest in WNT and SHH MBs, but lowest in Group 4 MB; Group 3 and Group 4 MBs have the largest number of cytotoxic lymphocytes and ECs [68].…”

“…Recent studies based on the quantification of gene expression signatures uncovered dramatical diversity of immune TME among the MB subgroups [68,69]. Of interest, SHH MB, but not Group 3 MB, displays strong signatures of macrophages and T cells, while Group 3 MB is enriched with the highest number of CD8 + T cells; PD-L1 expression is highest in WNT and SHH MBs, but lowest in Group 4 MB; Group 3 and Group 4 MBs have the largest number of cytotoxic lymphocytes and ECs [68]. Importantly, the study of murine SHH and Group 3 MB models further confirmed significantly higher percentages of infiltrating immune cells including tumor-associated macrophages (TAMs) in SHH tumors compared with Group 3 tumors; however, Group 3 tumors were enriched with more PD-1 + CD8 + T cells, resulting in a survival benefit in the Group 3 animals only after the treatment with PD-L1 and CTLA4 inhibitors [66].…”