Abstract
This study is directed at identifying the cell source(s) of immunomodulatory cytokines in high-grade gliomas and establishing whether the analysis of associated markers has implications for tumor grading. Glioma specimens classified as WHO grade II-IV by histopathology were assessed by gene expression analysis and immunohistochemistry to identify the cells producing interleukin (IL)-10, which was confirmed by flow cytometry and factor secretion in culture. Finally, principal component analysis (PCA) and mixture discriminant analysis (MDA) were used to investigate associations between expressed genes and glioma grade. The principle source of glioma-associated IL-10 is a cell type that bears phenotype markers consistent with M2 monocytes but does not express all M2-associated genes. Measures of expression of the M2 cell markers CD14, CD68, CD163, and CD204, which are elevated in high-grade gliomas, and the neutrophil/myeloid-derived suppressor cell (MDSC) subset marker CD15, which is reduced, provide the best index of glioma grade. Grade II and IV astrocytomas can be clearly differentiated on the basis of the expression of certain M2 markers in tumor tissues, whereas grade III astrocytomas exhibit a range of expression between the lower and higher grade specimens. The content of CD163(+) cells distinguishes grade III astrocytoma subsets with different prognosis.
Highlights
Gliomas account for approximately 50% of all primary brain neoplasms [1, 2], the most common being the highly malignant grade IV glioblastoma multiforme [3]
Higher grade astrocytomas express elevated levels of IL-10 and TGF-b and genes associated with the M2 monocyte phenotype
By comparison with epilepsy specimens, IL-10, TGF-b1, and TGF-b2 mRNA levels are significantly elevated in glioblastoma multiformes and there is a trend toward higher IL10, TGF-b1, and TGF-b2 mRNA levels in grade III astrocytoma (Fig. 1A)
Summary
Gliomas account for approximately 50% of all primary brain neoplasms [1, 2], the most common being the highly malignant grade IV glioblastoma multiforme [3]. Glioblastoma multiformes are aggressive, rapidly progressing, infiltrative, parenchymal neoplasms, with a poor prognosis [4]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Itably results in tumor recurrence [7, 8]. Given these clinical challenges and the refractory nature of glioblastoma multiformes, there is considerable interest in whether immune mechanisms may have therapeutic value [9, 10]
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