Increased immune gene expression and immune cell infiltration in high-grade astrocytoma distinguish long-term from short-term survivors

Abstract

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.

Figure 1

Representative histology of (A) greater than median tumor infiltration of cytotoxic T cells (CD8; red) and helper T-cells (CD4; brown) in long term survivor HGA11, and (B) greater than 75^th percentile tumor infiltration of microglia/macrophages (AIF1; brown) in long term survivor HGA12. Immunohistochemistry was performed using FFPE tumor sections with hematoxylin counterstaining (400x magnification). (C) Kaplan-Meier survival analysis of combined immune cell infiltration. High combined immune cell infiltration was defined as greater than median cytotoxic T-cell or helper T-cell or greater than 75^th percentile microglia/macrophage infiltration. Thirty three HGA samples were used.