Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level

Justyna Kmiecik; Aurélie Poli; Nicolaas H.C. Brons; Andreas Waha; Geir Egil Eide; Per Øyvind Enger; Jacques Zimmer; Martha Chekenya

doi:10.1016/j.jneuroim.2013.08.013

Elevated CD3⁺ and CD8⁺ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level

Justyna Kmiecik, Aurélie Poli, Nicolaas H.C. Brons, Andreas Waha, Geir Egil Eide, Per Øyvind Enger, Jacques Zimmer, Martha Chekenya^*

^*Corresponding author for this work

Neuro-Immunology Group

Research output: Contribution to journal › Article › Research › peer-review

314 Citations (Scopus)

Abstract

We characterized GBM patients' tumor and systemic immune contexture with aim to reveal the mechanisms of immunological escape, their impact on patient outcome, and identify targets for immunotherapy. Increased CD3⁺ T-cell infiltration was associated with prolonged survival independent of age, MGMT promoter methylation and post-operative treatment that implies potential for immunotherapy for GBM. Several mechanisms of escape were identified: within the tumor microenvironment: induced CD8⁺CD28^-Foxp3⁺ T_regs that may tolerize antigen presenting cells, elevated CD73 and CD39 ectonucleotidases that suppress T-cell function, and at the systemic level: elevated IL-10 levels in serum, diminished helper T-cell counts, and upregulated inhibitory CTLA-4.

Original language	English
Pages (from-to)	71-83
Number of pages	13
Journal	Journal of Neuroimmunology
Volume	264
Issue number	1-2
DOIs	https://doi.org/10.1016/j.jneuroim.2013.08.013
Publication status	Published - 2013

Keywords

Antigen presenting cells
GBM
Regulatory T cells
Tumor infiltrating cells

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Kmiecik, J., Poli, A., Brons, N. H. C., Waha, A., Eide, G. E., Enger, P. Ø., Zimmer, J., & Chekenya, M. (2013). Elevated CD3⁺ and CD8⁺ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level. Journal of Neuroimmunology, 264(1-2), 71-83. https://doi.org/10.1016/j.jneuroim.2013.08.013

@article{39f5a2a2125b46ecb29300ffb6bc8339,

title = "Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level",

abstract = "We characterized GBM patients' tumor and systemic immune contexture with aim to reveal the mechanisms of immunological escape, their impact on patient outcome, and identify targets for immunotherapy. Increased CD3+ T-cell infiltration was associated with prolonged survival independent of age, MGMT promoter methylation and post-operative treatment that implies potential for immunotherapy for GBM. Several mechanisms of escape were identified: within the tumor microenvironment: induced CD8+CD28-Foxp3+ Tregs that may tolerize antigen presenting cells, elevated CD73 and CD39 ectonucleotidases that suppress T-cell function, and at the systemic level: elevated IL-10 levels in serum, diminished helper T-cell counts, and upregulated inhibitory CTLA-4.",

keywords = "Antigen presenting cells, GBM, Regulatory T cells, Tumor infiltrating cells",

author = "Justyna Kmiecik and Aur{\'e}lie Poli and Brons, {Nicolaas H.C.} and Andreas Waha and Eide, {Geir Egil} and Enger, {Per {\O}yvind} and Jacques Zimmer and Martha Chekenya",

note = "Funding Information: We thank the GBM patients and voluntary healthy donors that consented to donating their blood and tumor tissue for use in this research. This work was supported by The Norwegian Cancer Society ( PK01-2008-0093 ), The Meltzer Fond , The Norwegian Research Council FRIFORSK and The Bergen Medical Research Foundation . We also thank The National Genome Research Network NGFNplus, Brain Tumor Net (grant 01GS08187, SP8 ), of the German Ministry for Education and Research for their support. We are grateful to Bodil B. Hansen, Tove Johannsen, and Ingrid Gravdal for technical assistance. We thank Professor Rolf Bjerkvig for providing the laboratory infrastructure where our research was performed. Flow cytometric analyses were performed at Centre de Recherche Public de la Sant{\'e}, Luxembourg and at the Molecular Imaging Centre, University of Bergen, supported by the National Program for Research in Functional Genomics (FUGE) , funded by the Norwegian Research Council .",

year = "2013",

doi = "10.1016/j.jneuroim.2013.08.013",

language = "English",

volume = "264",

pages = "71--83",

journal = "Journal of Neuroimmunology",

issn = "0165-5728",

publisher = "Elsevier",

number = "1-2",

}

Kmiecik, J, Poli, A, Brons, NHC, Waha, A, Eide, GE, Enger, PØ, Zimmer, J & Chekenya, M 2013, 'Elevated CD3⁺ and CD8⁺ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level', Journal of Neuroimmunology, vol. 264, no. 1-2, pp. 71-83. https://doi.org/10.1016/j.jneuroim.2013.08.013

Elevated CD3⁺ and CD8⁺ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level. / Kmiecik, Justyna; Poli, Aurélie; Brons, Nicolaas H.C. et al.
In: Journal of Neuroimmunology, Vol. 264, No. 1-2, 2013, p. 71-83.

Research output: Contribution to journal › Article › Research › peer-review

TY - JOUR

T1 - Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level

AU - Kmiecik, Justyna

AU - Poli, Aurélie

AU - Brons, Nicolaas H.C.

AU - Waha, Andreas

AU - Eide, Geir Egil

AU - Enger, Per Øyvind

AU - Zimmer, Jacques

AU - Chekenya, Martha

N1 - Funding Information: We thank the GBM patients and voluntary healthy donors that consented to donating their blood and tumor tissue for use in this research. This work was supported by The Norwegian Cancer Society ( PK01-2008-0093 ), The Meltzer Fond , The Norwegian Research Council FRIFORSK and The Bergen Medical Research Foundation . We also thank The National Genome Research Network NGFNplus, Brain Tumor Net (grant 01GS08187, SP8 ), of the German Ministry for Education and Research for their support. We are grateful to Bodil B. Hansen, Tove Johannsen, and Ingrid Gravdal for technical assistance. We thank Professor Rolf Bjerkvig for providing the laboratory infrastructure where our research was performed. Flow cytometric analyses were performed at Centre de Recherche Public de la Santé, Luxembourg and at the Molecular Imaging Centre, University of Bergen, supported by the National Program for Research in Functional Genomics (FUGE) , funded by the Norwegian Research Council .

PY - 2013

Y1 - 2013

N2 - We characterized GBM patients' tumor and systemic immune contexture with aim to reveal the mechanisms of immunological escape, their impact on patient outcome, and identify targets for immunotherapy. Increased CD3+ T-cell infiltration was associated with prolonged survival independent of age, MGMT promoter methylation and post-operative treatment that implies potential for immunotherapy for GBM. Several mechanisms of escape were identified: within the tumor microenvironment: induced CD8+CD28-Foxp3+ Tregs that may tolerize antigen presenting cells, elevated CD73 and CD39 ectonucleotidases that suppress T-cell function, and at the systemic level: elevated IL-10 levels in serum, diminished helper T-cell counts, and upregulated inhibitory CTLA-4.

AB - We characterized GBM patients' tumor and systemic immune contexture with aim to reveal the mechanisms of immunological escape, their impact on patient outcome, and identify targets for immunotherapy. Increased CD3+ T-cell infiltration was associated with prolonged survival independent of age, MGMT promoter methylation and post-operative treatment that implies potential for immunotherapy for GBM. Several mechanisms of escape were identified: within the tumor microenvironment: induced CD8+CD28-Foxp3+ Tregs that may tolerize antigen presenting cells, elevated CD73 and CD39 ectonucleotidases that suppress T-cell function, and at the systemic level: elevated IL-10 levels in serum, diminished helper T-cell counts, and upregulated inhibitory CTLA-4.

KW - Antigen presenting cells

KW - GBM

KW - Regulatory T cells

KW - Tumor infiltrating cells

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U2 - 10.1016/j.jneuroim.2013.08.013

DO - 10.1016/j.jneuroim.2013.08.013

M3 - Article

C2 - 24045166

AN - SCOPUS:84886774000

SN - 0165-5728

VL - 264

SP - 71

EP - 83

JO - Journal of Neuroimmunology

JF - Journal of Neuroimmunology

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