Differential expression of checkpoint markers in the normoxic and hypoxic microenvironment of glioblastomas
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Differential expression of checkpoint markers in the normoxic and hypoxic microenvironment of glioblastomas. / Petterson, Stine Asferg; Sørensen, Mia Dahl; Burton, Mark; Thomassen, Mads; Kruse, Torben A.; Michaelsen, Signe Regner; Kristensen, Bjarne Winther.
In: Brain Pathology, Vol. 33, No. 1, e13111, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Differential expression of checkpoint markers in the normoxic and hypoxic microenvironment of glioblastomas
AU - Petterson, Stine Asferg
AU - Sørensen, Mia Dahl
AU - Burton, Mark
AU - Thomassen, Mads
AU - Kruse, Torben A.
AU - Michaelsen, Signe Regner
AU - Kristensen, Bjarne Winther
N1 - Publisher Copyright: © 2022 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.
PY - 2023
Y1 - 2023
N2 - Glioblastoma is the most common primary malignant brain tumor in adults with an overall survival of only 14.6 months. Hypoxia is known to play a role in tumor aggressiveness but the influence of hypoxia on the immune microenvironment is not fully understood. The aim of this study was to investigate the expression of immune-related proteins in normoxic and hypoxic tumor areas by digital spatial profiling. Tissue samples from 10 glioblastomas were stained with a panel of 40 antibodies conjugated to photo-cleavable oligonucleotides. The free oligo-tags from normoxic and hypoxic areas were hybridized to barcodes for digital counting. Differential expression patterns were validated by Ivy Glioblastoma Atlas Project (GAP) data and an independent patient cohort. We found that CD44, Beta-catenin and B7-H3 were upregulated in hypoxia, whereas VISTA, CD56, KI-67, CD68 and CD11c were downregulated. PD-L1 and PD-1 were not affected by hypoxia. Focusing on the checkpoint-related markers CD44, B7-H3 and VISTA, our findings for CD44 and VISTA could be confirmed with Ivy GAP RNA sequencing data. Immunohistochemical staining and digital quantification of CD44, B7-H3 and VISTA in an independent cohort confirmed our findings for all three markers. Additional stainings revealed fewer T cells and high but equal amounts of tumor-associated microglia and macrophages in both hypoxic and normoxic regions. In conclusion, we found that CD44 and B7-H3 were upregulated in areas with hypoxia whereas VISTA was downregulated together with the presence of fewer T cells. This heterogeneous expression should be taken into consideration when developing novel therapeutic strategies.
AB - Glioblastoma is the most common primary malignant brain tumor in adults with an overall survival of only 14.6 months. Hypoxia is known to play a role in tumor aggressiveness but the influence of hypoxia on the immune microenvironment is not fully understood. The aim of this study was to investigate the expression of immune-related proteins in normoxic and hypoxic tumor areas by digital spatial profiling. Tissue samples from 10 glioblastomas were stained with a panel of 40 antibodies conjugated to photo-cleavable oligonucleotides. The free oligo-tags from normoxic and hypoxic areas were hybridized to barcodes for digital counting. Differential expression patterns were validated by Ivy Glioblastoma Atlas Project (GAP) data and an independent patient cohort. We found that CD44, Beta-catenin and B7-H3 were upregulated in hypoxia, whereas VISTA, CD56, KI-67, CD68 and CD11c were downregulated. PD-L1 and PD-1 were not affected by hypoxia. Focusing on the checkpoint-related markers CD44, B7-H3 and VISTA, our findings for CD44 and VISTA could be confirmed with Ivy GAP RNA sequencing data. Immunohistochemical staining and digital quantification of CD44, B7-H3 and VISTA in an independent cohort confirmed our findings for all three markers. Additional stainings revealed fewer T cells and high but equal amounts of tumor-associated microglia and macrophages in both hypoxic and normoxic regions. In conclusion, we found that CD44 and B7-H3 were upregulated in areas with hypoxia whereas VISTA was downregulated together with the presence of fewer T cells. This heterogeneous expression should be taken into consideration when developing novel therapeutic strategies.
KW - digital spatial profiling
KW - glioblastoma
KW - hypoxia
KW - immune checkpoints
U2 - 10.1111/bpa.13111
DO - 10.1111/bpa.13111
M3 - Journal article
C2 - 36093941
AN - SCOPUS:85137851032
VL - 33
JO - Brain Pathology
JF - Brain Pathology
SN - 1015-6305
IS - 1
M1 - e13111
ER -
ID: 320645448