Characterization of Distinct Immunophenotypes across Pediatric Brain Tumor Types

Abstract

Despite increasing evidence that anti-tumor immune control exists in the pediatric brain, these findings have yet to be exploited successfully in the clinic. A barrier to development of immunotherapeutic strategies in pediatric brain tumors is that the immunophenotype of these tumors’ microenvironment has not been defined. To address this the present study used multicolor FACS of disaggregated tumor to systematically characterize the frequency and phenotype of infiltrating immune cells in the most common pediatric brain tumor types. The initial study cohort consisted of 7 pilocytic astrocytoma (PA), 19 ependymoma (EPN), 5 glioblastoma (GBM), 6 medulloblastoma (MED) and 5 non-tumor brain (NT) control samples obtained from epilepsy surgery. Immune cell types analyzed included both myeloid and T-cell lineages and respective markers of activated or suppressed functional phenotypes. Immune parameters that distinguished each of the tumor types were identified. PA and EPN demonstrated significantly higher infiltrating myeloid and lymphoid cells compared to GBM, MED or NT. Additionally, PA and EPN conveyed a comparatively activated/M1-skewed myeloid functional phenotype denoted in particular by HLA-DR and CD64 expression. In contrast, GBM and MED contained progressively fewer infiltrating leukocytes and more muted functional phenotype similar to that of NT. These findings were recapitulated using whole tumor expression of corresponding immune marker genes in a large gene expression microarray cohort of pediatric brain tumors. The results of this cross-tumor comparative analysis demonstrate that different pediatric brain tumor types exhibit distinct immunophenotypes, implying that specific immunotherapeutic approaches may be most effective for each tumor type.

In Vitro Modeling of Tissue-Specific 3D Microenvironments and Possibile Application to Pediatric Cancer Research

“…Thus, an antitumorigenic action for NCPs has been postulated. In vitro experiments seem to sustain this hypothesis, since cultured NPCs release soluble factors that can inhibit glioblastoma proliferation, induce differentiation and cell death [189]. Brain tumors are highly vascularised and this rich vascular network is not only a matter of tissue oxygenation, but, more importantly, of endothelial cells, pericyte, and astrocyte (the neurovascular system) presence, that support tumor progression.…”

“…It has been shown that the M1 phenotype, with anti-tumoral properties, is the most prevalent in low-grade CNS tumors, while the M2 phenotype, also designed as Tumor Associated Macrophages (TAMs) positively correlates with the histological malignancy of the tumor [188,189]. It has been demonstrated that TAMs promote glioma cell proliferation, as well as angiogenesis and invasion [190,191].…”

“…This microanatomical structure, designed as perivascular niche (PVN), contain stem cells in both normal and brain tumoral tissues. This complex network of cells allows multiple interactions, promoting CSCs proliferation, enhancing their survival, and protecting them from chemotherapy [187,189].…”

Dual roles for immune metagenes in breast cancer prognosis and therapy prediction

“…Often revealed by hierarchical clustering techniques or outcome correlation studies, these signatures distinguish multiple different immune cell types [32][33][34][35][36][37] and recapitulate immunohistochemistry-based observations in breast cancer that link tumor-infiltrating immune cell abundance to disease-free survival and overall survival of patients [30,[36][37][38][39][40][41][42]. More recently, similar studies involving presurgical breast tumor biopsies have begun to demonstrate associations between immunity-related genes and tumor responsiveness to neoadjuvant chemotherapy [22,44,45,63,64].…”

“…In more recent years, microarray expression profiling studies in breast and other tumor types have identified immune gene signatures from whole tumor RNA extracts that reflect the abundance of tumor-infiltrating immune cells [30][31][32][33][34][35][36][37][38]. We and others have found that the biological and phenotypic properties of the genes comprising these signatures implicate distinct immune cell lineages [34][35][36][37]39,40], and that combinations of these immune genes correlate with patient outcomes ranging from recurrence-free survival [30,32,[36][37][38][39][40][41][42][43] to tumor regression in the neoadjuvant setting [44][45][46][47].…”