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. 2022 Aug;159(1):103-115.
doi: 10.1007/s11060-022-04047-y. Epub 2022 Jun 18.

Pre-surgery immune profiles of adult glioma patients

Paige M Bracci  1 , Terri Rice  2 , Helen M Hansen  2 , Stephen S Francis  2 , Sean Lee  2 , Lucie S McCoy  2 , Pavan P Shrestha  2 , Gayathri Warrier  2 , Jennifer L Clarke  2   3 , Annette M Molinaro  4   2 , Jennie W Taylor  2   3 , John K Wiencke  2 , Margaret R Wrensch  2
Affiliations

Pre-surgery immune profiles of adult glioma patients

Paige M Bracci et al. J Neurooncol. 2022 Aug.

Abstract

Introduction: Although immunosuppression is a known characteristic of glioma, no previous large studies have reported peripheral blood immune cell profiles prior to patient surgery and chemoradiation. This report describes blood immune cell characteristics and associated variables prior to surgery among typical glioma patients seen at a large University practice.

Methods: We analyzed pre-surgery blood samples from 139 glioma patients diagnosed with a new or recurrent grade II/III glioma (LrGG, n = 64) or new glioblastoma (GBM, n = 75) and 454 control participants without glioma. Relative cell fractions of CD4, CD8, B-cells, Natural Killer cells, monocytes, and neutrophils, were estimated via a validated deconvolution algorithm from blood DNA methylation measures from Illumina EPIC arrays.

Results: Dexamethasone use at time of blood draw varied by glioma type being highest among patients with IDH wild-type (wt) GBM (75%) and lowest for those with oligodendroglioma (14%). Compared to controls, glioma patients showed statistically significant lower cell fractions for all immune cell subsets except for neutrophils which were higher (all p-values < 0.001), in part because of the higher prevalence of dexamethasone use at time of blood draw for IDHwt GBM. Patients who were taking dexamethasone were more likely to have a low CD4 count (< 200, < 500), increased neutrophils, low absolute lymphocyte counts, higher total cell count and higher NLR.

Conclusion: We show that pre-surgery blood immune profiles vary by glioma subtype, age, and more critically, by use of dexamethasone. Our results highlight the importance of considering dexamethasone exposures in all studies of immune profiles and of obtaining immune measures prior to use of dexamethasone, if possible.

Keywords: Deconvolution methods; Dexamethasone; Glioblastoma; Immune cell subset; Lower grade glioma; Methylation.

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Conflict of interest statement

JKW is a cofounder of Cellintec, which played no role in the current study. He has no financial disclosure or conflict of interest related to the material and research in this paper.

Figures

Fig. 1
Fig. 1
Distribution of specific cell subtype fractions by glioma WHO 2016 Classification among Immune Profile Study (IPS) Glioma patients. Boxplots of immune cell subset fractions [B cell, CD4 T cell (CD4), CD8 T cell (CD8), NK cells, Neutrophils, Total Lymphocytes] for Immune Profile Study (IPS) glioma patients grouped by WHO 2016 Glioma Classification. The median is represented by the solid line within each box, each box represents 50% of the data for that group, the vertical line emerging above the box represents the top 25% of the data spread and the vertical line emerging from the bottom of each box represents the lowest 25% of the data spread. The number of patients in each group are provided in the boxplot. The Kruskal–Wallis p-value is for the test of an overall difference in immune cell subset fraction among the four groups. p-Values for pairwise comparisons are depicted by brackets with the groups at each end of the bracket being compared. In general, immune cell fractions differed between IDHwt GBM and other glioma subtypes (lower in IDHwt GBM apart from neutrophils which were higher) whereas differences were not observed between other glioma subtypes (depicted by red circles in cell subtype plot)
Fig. 2
Fig. 2
Boxplots for the comparisons of immune cell subset fractions among Immune Profile Study (IPS) glioma patients and Adult Glioma Study (AGS) controls by dexamethasone use at the time of blood draw. Boxplots of the distribution of fractions of specific immune cell subsets (B cells, CD4 T cells, CD8 T cells, NK cells, Neutrophils, Total Lymphocytes) for IPS glioma cases and AGS controls by dexamethasone use. The median is represented by the solid line within each box, each box represents 50% of the data for that group, the line emerging above the box represents the top 25% of the data spread and the line emerging from the bottom of each box represents the lowest 25% of the data spread. The number of persons in each group are provided in the boxplot. The Kruskal–Wallis p-value is for the test of an overall difference among the three groups (AGS controls, IPS glioma cases who used dexamethasone, IPS glioma cases who did not use dexamethasone) within each immune cell subset. Pairwise comparisons are depicted by brackets with the groups at each end of the bracket being compared and the p-value for that difference indicated on top of the bracket
Fig. 3
Fig. 3
Neutrophil cell fractions for dexamethasone use at blood draw by WHO 2016 Classification of Immune Profile Study (IPS) Glioma Cases, and Adult Glioma Study (AGS) Controls (no DEX). Boxplots of neutrophil fractions for IPS glioma cases grouped by WHO 2016 Glioma Classification and DEX status, and AGS controls who did not use DEX. The median is represented by the solid line within each box, each box represents 50% of the data for that group, the line emerging above the box represents the top 25% of the data spread and the line emerging from the bottom of each box represents the lowest 25% of the data spread. The horizontal broken line represents the median neutrophil fraction among AGS controls. The number of patients or controls in each group are provided in the boxplot. The Kruskal–Wallis p-value is for the test of an overall difference in neutrophil fraction among the nine groups
Fig. 4
Fig. 4
Heatmap of Z-scores from pairwise comparisons of immune cell subset fractions among Adult Glioma Study (AGS) controls (none taking DEX) and Immune Profiles Study (IPS) Glioma patients by WHO 2016 Classification and DEX use at blood draw. Heatmap of Z-score values from pairwise comparisons (Dunn test) of immune cell subset fractions among IPS Glioma patients classified per WHO 2016 Classification and DEX status, and AGS controls (no DEX). Row labels (right side of plot) indicate the groups being compared (controls and glioma cases) and the number in each group. Column labels (bottom of plot) indicate the specific immune cell subset Z-score that is being depicted for the comparisons made (CD4_z = CD4 T cells, Neu_z = Neutrophils, nlr_z = Neutrophil to Lymphocyte Ratio, tL_z = Total Lymphocytes, lmr_z = Lymphocyte to Monocyte Ratio, CD8_z = CD8 T cells, B_z = B cells, NK_z = Natural Killer cells, Mono_z = Monocytes). Each block represents the Z score for the comparison of an immune cell subset fraction between two groups of patients noted in the right-hand margin of the map e.g., the left-most square in the top row represents the Z score for the comparison of CD4 T cell fraction values between AGS controls (no DEX) and IPS glioma patients with IDHmt 1p19q co-deleted oligodendroglioma (used DEX). Darker green blocks represent higher Z scores and as shown, most statistically significant differences (denoted as *p 
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