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Journal of Neuro-Oncology

, Volume 141, Issue 1, pp 95–102 | Cite as

RNA-seq for identification of therapeutically targetable determinants of immune activation in human glioblastoma

  • Stephen J. BagleyEmail author
  • Wei-Ting Hwang
  • Steven Brem
  • Gerald P. Linette
  • Donald M. O’Rourke
  • Arati S. Desai
Clinical Study

Abstract

Introduction

We sought to determine which therapeutically targetable immune checkpoints, costimulatory signals, and other tumor microenvironment (TME) factors are independently associated with immune cytolytic activity (CYT), a gene expression signature of activated effector T cells, in human glioblastoma (GBM).

Methods

GlioVis was accessed for RNA-seq data from The Cancer Genome Atlas (TCGA). For subjects with treatment-naïve, primary GBM, we quantified mRNA expression of 28 therapeutically targetable TME factors. CYT (geometric mean of GZMA and PRF1 expression) was calculated for each tumor. Multiple linear regression was performed to determine the relationship between the dependent variable (CYT) and mRNA expression of each of the 28 factors. Variables associated with CYT in multivariate analysis were subsequently evaluated for this association in an independent cohort of newly diagnosed GBMs from the Chinese Glioma Cooperative Group (CGCG).

Results

109 TCGA tumors were analyzed. The final multiple linear regression model included the following variables, each positively associated with CYT except VEGF-A (negative association): CSF-1 (p = 0.003), CD137 (p = 0.042), VEGF-A (p < 0.001), CTLA4 (p = 0.028), CD40 (p = 0.023), GITR (p = 0.020), IL6 (p = 0.02), and OX40 (p < 0.001). In CGCG (n = 52), each of these variables remained significantly associated with CYT in univariate analysis except for VEGF-A. In multivariate analysis, only CTLA4 and CD40 remained statistically significant.

Conclusions

Using multivariate modeling of RNA-seq gene expression data, we identified therapeutically targetable TME factors that are independently associated with intratumoral cytolytic T-cell activity in human GBM. As a myriad of systemic immunotherapies are now available for investigation, our results could inform rational combinations for evaluation in GBM.

Keywords

Glioblastoma T cells RNA-seq Immunotherapy 

Notes

Acknowledgements

The results published here are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Research involving human participants and/or animals

This article does not contain any studies with human participants or animals performed by any of the authors.

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Hematology/Oncology, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  2. 2.Department of Biostatistics, Epidemiology, and Informatics, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Department of Neurosurgery, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA

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