Prognostic relevance of tumor-infiltrating lymphocytes and immune checkpoints in pediatric medulloblastoma

Abstract

Pediatric medulloblastomas are the most frequently diagnosed embryonal tumors of the central nervous system. Current therapies cause severe neurological and cognitive side effects including secondary malignancies. Cellular immunotherapy might be key to improve survival and to avoid morbidity. Efficient killing of tumor cells using immunotherapy requires to overcome cancer-associated strategies to evade cytotoxic immune responses. Here, we examined the immune response and immune evasion strategies in pediatric medulloblastomas. Cytotoxic T-cells, infiltrating medulloblastomas with variable activation status, showed no correlation with overall survival of the patients. We found limited numbers of PD1+ T-cells and complete absence of PD-L1 on medulloblastomas. Medulloblastomas downregulated immune recognition molecules MHC-I and CD1 d. Intriguingly, expression of granzyme inhibitors SERPINB1 and SERPINB4 was acquired in 23% and 50% of the tumors, respectively. Concluding, pediatric medulloblastomas exploit multiple immune evasion strategies to overcome immune surveillance. Absence of PD-L1 expression in medulloblastoma suggest limited or no added value for immunotherapy with PD1/PD-L1 blockers.

Subgroup-specific immune and stromal microenvironment in medulloblastoma

“…Although this is the largest series of medulloblastomas stained for PD-L1 currently reported, we did not find membranous PD-L1 expression in more than 1% of tumor cells in any of the studied samples. This confirms previous studies, 21,22 which did not see PD-L1 expression in medulloblastoma and contradicts a small study by Murata et al 20 reporting PD-L1 expression in 9/16 samples. Hence, immunohistological staining of PD-L1 cannot be used as a predictive biomarker for checkpoint inhibition.…”

“…In a cohort including 16 tumors, Murata et al reported that high expression of PD-L1 (seen in 56% of the cases) was associated with low CD8C T cell infiltration and poor prognosis in medulloblastoma. 20 In contrast, Majzner et al 21 (40 cases) and Vermeulen et al 22 (29 cases) did not see PD-L1 expression in any of the studied medulloblastomas. None of the last three studies found subgroup-specific patterns of tumor-infiltrating lymphocytes (TILs).…”

“…Previous reports were limited by low sample sizes and/or focused on only one or two cell populations. 16,[18][19][20][21][22] Hence, to gain a more comprehensive overview, we used a state of the art bioinformatics method to quantify eight immune cell populations and two stromal cell populations as well as PD-L1 in a pancancer dataset of 1422 brain tumors and a medulloblastoma dataset including 763 samples. This allows for the simultaneous characterization of several cell populations and overcomes the described limitations.…”

“…It corroborates findings by Vermeulen et al, who did not see associations between TILs and prognosis. 22 In contrast, peripheral levels of TH1 cells were associated with better prognosis already in a small cohort of medulloblastoma. 42 Hence, a simultaneous investigation of peripheral and intratumoral immune cells seems to be of key relevance in further studies of medulloblastoma tumor immunology.…”

Total tumor RNA pulsed dendritic cells plus adoptive transfer of ex-vivo enriched autologous T-lymphocytes in the treatment of children with primary brain tumors

“…An IHC analysis of the antigen processing machinery (APM) in astrocytic tumors (4 each of grade I-IV gliomas) revealed down regulation of the APM proteins LMP-2, TAP1, and β2 microglobulin without change in the surface human leukocyte antigen (HLA)-class I protein expression [34] . In 26 medulloblastoma samples, Vermeulen et al [35] found CD3+ T cell intratumoral and/or perivascular in distribution. The number of CD3+ tumor infiltrating lymphocytes (TILs) was at a median of 23.5 per 2 mm3 of tumor tissue.…”