TY - JOUR
T1 - Distribution and prognostic impact of microglia/macrophage subpopulations in gliomas
AU - Zeiner, Pia S.
AU - Preusse, Corinna
AU - Golebiewska, Anna
AU - Zinke, Jenny
AU - Iriondo, Ane
AU - Muller, Arnaud
AU - Kaoma, Tony
AU - Filipski, Katharina
AU - Müller-Eschner, Monika
AU - Bernatz, Simon
AU - Blank, Anna Eva
AU - Baumgarten, Peter
AU - Ilina, Elena
AU - Grote, Anne
AU - Hansmann, Martin L.
AU - Verhoff, Marcel A.
AU - Franz, Kea
AU - Feuerhake, Friedrich
AU - Steinbach, Joachim P.
AU - Wischhusen, Jörg
AU - Stenzel, Werner
AU - Niclou, Simone P.
AU - Harter, Patrick N.
AU - Mittelbronn, Michel
N1 - Funding Information:
PSZ obtained grants from Patenschaftsmodell Universität Frankfurt (an intramural funding that was attributed for this project for PSZ, grant number F11/14_R114/2014) during the conduct of the study. MM would like to thank the Luxembourg National Research Fund (FNR) for the support (FNR PEARL P16/BM/11192868 grant). ILUMINATE (FKZ:031 B0006C) funded by German Ministry for Education and Research (BMBF), Project Management Juelich (PTJ), supported AG and FF. We thank C. Penski, M. Dunst and T. Starzetz for technical support. We thank S. Reiß and S. Pennartz from Miltenyi Biotec for technical advice and support concerning the MACS® isolation of primary human M/M.
Funding Information:
PSZ obtained grants from Patenschaftsmodell Universität Frankfurt (an intramural funding that was attributed for this project for PSZ, grant number F11/14_R114/2014) during the conduct of the study. MM would like to thank the Luxembourg National Research Fund (FNR) for the support (FNR PEARL P16/BM/11192868 grant). ILUMINATE (FKZ:031 B0006C) funded by German Ministry for Education and Research (BMBF), Project Management Juelich (PTJ), supported AG and FF.
Publisher Copyright:
© 2018 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology
PY - 2019/7
Y1 - 2019/7
N2 - While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma-associated microglia/macrophages (GAMs), on patients’ clinical course is still unclear. Thus, we aimed at assessing the immunohistochemical expression of selected microglia and macrophage markers in 344 gliomas (including gliomas from WHO grade I–IV). Furthermore, we analyzed a cohort of 241 IDH1R132H-non-mutant GBM patients for association of GAM subtypes and patient overall survival. Phenotypical properties of GAMs, isolated from high-grade astrocytomas by CD11b-based magnetic cell sorting, were analyzed by immunocytochemistry, mRNA microarray, qRT-PCR and bioinformatic analyses. A higher amount of CD68-, CD163- and CD206-positive GAMs in the vital tumor core was associated with beneficial patient survival. The mRNA expression profile of GAMs displayed an upregulation of factors that are considered as pro-inflammatory M1 (eg, CCL2, CCL3L3, CCL4, PTGS2) and anti-inflammatory M2 polarization markers (eg, MRC1, LGMN, CD163, IL10, MSR1), the latter rather being associated with phagocytic functions in the GBM microenvironment. In summary, we present evidence that human GBMs contain mixed M1/M2-like polarized GAMs and that the levels of different GAM subpopulations in the tumor core are positively associated with overall survival of patients with IDH1R132H-non-mutant GBMs.
AB - While the central nervous system is considered an immunoprivileged site and brain tumors display immunosuppressive features, both innate and adaptive immune responses affect glioblastoma (GBM) growth and treatment resistance. However, the impact of the major immune cell population in gliomas, represented by glioma-associated microglia/macrophages (GAMs), on patients’ clinical course is still unclear. Thus, we aimed at assessing the immunohistochemical expression of selected microglia and macrophage markers in 344 gliomas (including gliomas from WHO grade I–IV). Furthermore, we analyzed a cohort of 241 IDH1R132H-non-mutant GBM patients for association of GAM subtypes and patient overall survival. Phenotypical properties of GAMs, isolated from high-grade astrocytomas by CD11b-based magnetic cell sorting, were analyzed by immunocytochemistry, mRNA microarray, qRT-PCR and bioinformatic analyses. A higher amount of CD68-, CD163- and CD206-positive GAMs in the vital tumor core was associated with beneficial patient survival. The mRNA expression profile of GAMs displayed an upregulation of factors that are considered as pro-inflammatory M1 (eg, CCL2, CCL3L3, CCL4, PTGS2) and anti-inflammatory M2 polarization markers (eg, MRC1, LGMN, CD163, IL10, MSR1), the latter rather being associated with phagocytic functions in the GBM microenvironment. In summary, we present evidence that human GBMs contain mixed M1/M2-like polarized GAMs and that the levels of different GAM subpopulations in the tumor core are positively associated with overall survival of patients with IDH1R132H-non-mutant GBMs.
KW - glioma
KW - glioma-associated microglia and macrophages
KW - immune polarization
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85067383704&partnerID=8YFLogxK
UR - https://www.ncbi.nlm.nih.gov/pubmed/30506802
U2 - 10.1111/bpa.12690
DO - 10.1111/bpa.12690
M3 - Article
C2 - 30506802
AN - SCOPUS:85067383704
SN - 1015-6305
VL - 29
SP - 513
EP - 529
JO - Brain Pathology
JF - Brain Pathology
IS - 4
ER -