Immune cell infiltrate differences in pilocytic astrocytoma and glioblastoma: evidence of distinct immunological microenvironments that reflect tumor biology.
ABSTRACT The tumor microenvironment in astrocytomas is composed of a variety of cell types, including infiltrative inflammatory cells that are dynamic in nature, potentially reflecting tumor biology. In this paper the authors demonstrate that characterization of the intratumoral inflammatory infiltrate can distinguish high-grade glioblastoma from low-grade pilocytic astrocytoma.
Tumor specimens from ninety-one patients with either glioblastoma or pilocytic astrocytoma were analyzed at the University of California, San Francisco. A systematic neuropathology analysis was performed. All tissue was collected at the time of the initial surgery prior to adjuvant treatment. Immune cell infiltrate not associated with necrosis or hemorrhage was analyzed on serial 4-μm sections. Analysis was performed for 10 consecutive hpfs and in 3 separate regions (total 30 × 0.237 mm(2)). Using immunohistochemistry for markers of infiltrating cytotoxic T cells (CD8), natural killer cells (CD56), and macrophages (CD68), the inflammatory infiltrates in these tumors were graded quantitatively and classified based on microanatomical location (perivascular vs intratumoral). Control markers included CD3, CD20, and human leukocyte antigen.
Glioblastomas exhibited significantly higher perivascular (CD8) T-cell infiltration than pilocytic astrocytomas (62% vs 29%, p = 0.0005). Perivascular (49%) and intratumoral (89%; p = 0.004) CD56-positive cells were more commonly associated with glioblastoma. The CD68-positive cells also were more prevalent in the perivascular and intratumoral space in glioblastoma. In the intratumoral space, all glioblastomas exhibited CD68-positive cells compared with 86% of pilocytic astrocytomas (p = 0.0014). Perivascularly, CD68-positive infiltrate was also more prevalent in glioblastoma when compared with pilocytic astrocytoma (97% vs 86%, respectively; p = 0.0003). The CD3-positive, CD20-positive, and human leukocyte antigen-positive infiltrates did not differ between glioblastoma and pilocytic astrocytoma.
This analysis suggests a significantly distinct immune profile in the microenvironment of high-grade glioblastoma versus low-grade pilocytic astrocytoma. This difference in tumor microenvironment may reflect an important difference in the tumor biology of glioblastoma.
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ABSTRACT: Tumour-associated macrophages (TAMs) are enriched in glioblastoma multiformes (GBMs) that contain glioma stem cells (GSCs) at the apex of their cellular hierarchy. The correlation between TAM density and glioma grade suggests a supportive role for TAMs in tumour progression. Here we interrogated the molecular link between GSCs and TAM recruitment in GBMs and demonstrated that GSCs secrete periostin (POSTN) to recruit TAMs. TAM density correlates with POSTN levels in human GBMs. Silencing POSTN in GSCs markedly reduced TAM density, inhibited tumour growth, and increased survival of mice bearing GSC-derived xenografts. We found that TAMs in GBMs are not brain-resident microglia, but mainly monocyte-derived macrophages from peripheral blood. Disrupting POSTN specifically attenuated the tumour-supportive M2 type of TAMs in xenografts. POSTN recruits TAMs through the integrin αvβ3 as blocking this signalling by an RGD peptide inhibited TAM recruitment. Our findings highlight the possibility of improving GBM treatment by targeting POSTN-mediated TAM recruitment.Nature Cell Biology 01/2015; · 20.06 Impact Factor