Increased immune gene expression and immune cell infiltration in high-grade astrocytoma distinguish long-term from short-term survivors.
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.
Department of Pediatrics, University of Colorado Denver, Aurora, CO 80045, USA. andrew.donson@ucdenver.edu
Andrew M
AM
Donson
Diane K
DK
Birks
Stephanie A
SA
Schittone
Bette K
BK
Kleinschmidt-DeMasters
Derrick Y
DY
Sun
Molly F
MF
Hemenway
Michael H
MH
Handler
Allen E
AE
Waziri
Michael
M
Wang
Nicholas K
NK
Foreman
D001254:Astrocytoma / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D001932:Brain Neoplasms / Q000235:genetics* / Q000276:immunology* / Q000401:mortality; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D017567:Karnofsky Performance Status; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D016016:Proportional Hazards Models; D017741:Survivors