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Analysis of immunobiologic markers in primary and recurrent glioblastoma

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Abstract

Glioblastoma (GBM) generates a varied immune response and understanding the immune microenvironment may lead to novel immunotherapy treatments modalities. The goal of this study was to evaluate the expression of immunologic markers of potential clinical significance in primary versus recurrent GBM and assess the relationship between these markers and molecular characteristics of GBM. Human GBM samples were evaluated and analyzed with immunohistochemistry for multiple immunobiologic markers (CD3, CD8, FoxP3, CD68, CD163, PD1, PDL1, CTLA4, CD70). Immunoreactivity was analyzed using Aperio software. Degree of strong positive immunoreactivity within the tumor was compared to patient and tumor characteristics including age, gender, MGMT promoter methylation status, and ATRX, p53, and IDH1 mutation status. Additionally, the TCGA database was used to perform similar analysis of these factors in GBM using RNA-seq by expectation–maximization. Using odds ratios, IDH1 mutated GBM had statistically significant decreased expression of CD163 and CD70 and a trend for decreased PD1, CTLA4, and Foxp3. ATRX-mutated GBMs exhibited statistically significant increased CD3 immunoreactivity, while those with p53 mutations were found to have significantly increased CTLA4 immunoreactivity. The odds of having strong CD8 and CD68 reactivity was significantly less in MGMT methylated tumors. No significant difference was identified in any immune marker between the primary and recurrent GBM, nor was a significant change in immunoreactivity identified among age intervals. TCGA analysis corroborated findings related to the differential immune profile of IDH1 mutant, p53 mutant, and MGMT unmethylated tumors. Immunobiologic markers have greater association with the molecular characteristics of the tumor than with primary/recurrent status or age.

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Acknowledgements

This work was funded by the Florida Center for Brain Tumor Research. We would like to acknowledge Barbara Frentzen for her work in obtaining samples for analysis through the FCBTR.

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Author notes

  1. Maryam Rahman and Jesse Kresak are co first authors.

Authors and Affiliations

  1. Department of Pathology, University of Florida, Gainesville, FL, USA

    Jesse Kresak & Wesley Hiser

  2. Department of Neurosurgery, University of Florida, Gainesville, FL, USA

    Maryam Rahman, Changlin Yang, Jianping Huang, Paul Kubilis & Duane Mitchell

  3. University of Florida Brain Tumor Immunotherapy Program, University of Florida, Gainesville, FL, USA

    Maryam Rahman, Jesse Kresak, Changlin Yang, Jianping Huang, Paul Kubilis & Duane Mitchell

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  1. Maryam Rahman
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  2. Jesse Kresak
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Correspondence to Maryam Rahman.

Electronic supplementary material

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11060_2017_2732_MOESM1_ESM.tif

Supplementary Figure 1. Effect of Recurrent versus Primary tumor status on immune marker expression. Circled odds ratio point estimates differ significantly from one at α=0.05 (TIF 190 KB)

11060_2017_2732_MOESM2_ESM.tif

Supplementary Figure 2. Change in Immune Marker Expression per 10-Year Age Increase. Circled odds ratio point estimates differ significantly from one at α=0.05 (TIF 192 KB)

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Rahman, M., Kresak, J., Yang, C. et al. Analysis of immunobiologic markers in primary and recurrent glioblastoma. J Neurooncol 137, 249–257 (2018). https://doi.org/10.1007/s11060-017-2732-1

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  • DOI: https://doi.org/10.1007/s11060-017-2732-1

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