Term Survivors Astrocytoma Distinguish Long - Term from Immune Cell Infiltration in High - Grade Increased Immune

Survival in the majority of high-grade astrocytoma (HGA) patients is very poor, with only a rare population of long-term survivors. A better understanding of the biological factors associated with long-term survival in HGA would aid development of more effective therapy and survival prediction. Factors associated with long-term survival have not been extensively studied using unbiased genome-wide expression analyses. In the current study, gene expression microarray profiles of HGA from long-term survivors were interrogated for discovery of survival-associated biological factors. Ontology analyses revealed that increased expression of immune function-related genes was the predominant biological factor that positively correlated with longer survival. A notable T cell signature was present within this prognostic immune gene set. Using immune cell-specific gene classifiers, both T cell-associated and myeloid linage-associated genes were shown to be enriched in HGA from long-term versus short-term survivors. Association of immune function and cell-specific genes with survival was confirmed independently in a larger publicly available glioblastoma gene expression microarray data set. Histology was used to validate the results of microarray analyses in a larger cohort of long-term survivors of HGA. Multivariate analyses demonstrated that increased immune cell infiltration was a significant independent variable contributing to longer survival, as was Karnofsky/Lansky performance score. These data provide evidence of a prognostic anti-tumor adaptive immune response and rationale for future development of immunotherapy in HGA. M edian survival in high-grade astrocytoma (HGA), consisting predominantly of glioblastoma (GBM) and an-aplastic astrocytoma (AA), is 15 mo and 3 y, respectively (1, 2). Few robust prognostic factors have been identified in HGA, hindering patient care and stratification in clinical trials. Currently established clinical risk factors include Karnofsky/Lansky performance score, a measure of patient well-being that is widely used in oncology, and age (3). O-6-Methylguanine-DNA methyltransfer-ase promoter methylation status and isocitrate dehydrogenase 1 mutational status have been established as molecular prognostic factors in adult HGA (4, 5). Gene expression microarray analyses have been used to identify novel prognostic biomarkers in HGA. This unbiased genome-wide approach has the additional benefit of providing insight into the biological mechanisms of tumorigenesis that can be exploited for the development of more effective therapies. Despite numerous studies that have identified prognostic gene signatures in HGA using microarray technology, there remains no predictor of survival that has proved robustly reproducible from study to study (6–10). This may be due to the effects of biological heterogeneity inherent in HGA combined with the typically limited duration …