Fondation MEDIC

The impact of glioblastoma adaptation to hypoxia on anti-tumour immunity
Project leader – Paul R Walker
Paul R Walker

Paul R Walker obtained his PhD in immunology, under the direction of Thomas Lehner at the University of London in 1992. He then moved to the Lausanne Branch of the Ludwig Institute for Cancer Research for postdoctoral studies in the antigen recognition group of Janet Maryanski. Since 1995 he has been working in cancer research at Geneva University Hospitals and the University of Geneva, co-heading the laboratory of tumour immunology with Prof. P-Y Dietrich. In 2001 he obtained his Privat Docent and from 2006 he has been Senior Lecturer in the Department of Internal Medicine Specialties at the Faculty of Medicine. He currently leads the Immunobiology of Brain Tumours group and focuses his research on the specialized tumour-immune interactions occurring in the central nervous system and how to exploit these in the context of immunotherapies.

Service d’Oncologie,
Hôpitaux Universitaires de Genève
24 rue Micheli-du Crest
1211 Geneva 14

Phone: +41 22 372 98 80

Web page

Group members

Romain Vuillefroy de Silly, PhD

postdoctoral fellow

Wilma di Berardino Besson, PhD

senior scientist

Patrick Teta


Céline Yacoub Maroun


Cristina Riccadonna

graduate student

Leticia Barba

graduate student

Marta Calvo Tardón

graduate student

Project description

Malignant gliomas are heterogeneous brain tumours with poor prognosis, even with best current treatment comprising surgical resection and radiochemotherapy. Cell-mediated immunotherapies are currently being evaluated, but the details of tumour-immune cell interactions at the brain tumour site remain to be fully elucidated. A major microenvironmental factor is tissue oxygenation, ranging from around 5% O2 to less than 1% in hypoxic zones. The consequences of hypoxia on glioma cell biology have been intensively studied, but how this affects therapeutic immunity is unclear. The principle aim of this project is therefore to determine how glioma responses to physiological normoxia and hypoxia impact on anti-tumour immunity. Importantly, in a parallel project, tumour-specific CD8+ T cells retained cytolytic capacity against tumour at both 1% and 5% O2.

Preliminary transcriptional profiling of immune-related genes of three human glioma cell lines revealed hypoxia regulated modulation of multiple immune-related genes, but with mostly unique profiles for each cell line. In this project we are extending analysis of the role of oxygen tension in modulating immune-related gene expression in a larger number of glioma cell lines, including early passage lines and neurosphere cultures. Gene expression modulation by hypoxia will be assessed not only with reference to atmospheric oxygen, but also to the more relevant physiological oxygen fraction of 5% O2. Modulated genes will be validated for protein expression, and assessed for impact on immune responses using in vitro tests with autologous human immune cells, and in vivo in either xenografted mice or in mice engineered to express homologous proteins.

The hypoxic niche within the tumour bed is particularly important because of the correlation of hypoxia with malignancy. The anticipated results of this project will help to understand whether this microenvironmental feature will impact on current attempts to employ immunotherapy for malignant glioma.

2015 / 10.1002/eji.201445284
Vuillefroy de Silly R, Ducimetière L, Yacoub Maroun C, Dietrich PY, Derouazi M, Walker P. Phenotypic switch of CD8(+) T cells reactivated under hypoxia toward IL-10 secreting, poorly proliferative effector cells. Eur J Immunol. 2015 Aug;45(8):2263-75
» PubMed
2015 / doi: 10.1158/0008-5472.CAN-14-3017
Derouazi M, Di Berardino-Besson W, Belnoue E, Hoepner S, Walther R, Benkhoucha M, Teta P, Dufour Y, Yacoub Maroun C, Salazar AM, Martinvalet D, Dietrich PY, Walker PR. Novel Cell-Penetrating Peptide-Based Vaccine Induces Robust CD4+ and CD8+ T Cell-Mediated Antitumor Immunity. Cancer Res. 2015 Aug 1;75(15):3020-31
» PubMed
2014 / 10.14694/EdBook_AM.2014.34.51
Dietrich PY, Dutoit V, Walker PR. Immunotherapy for glioma: from illusion to realistic prospects?. Am Soc Clin Oncol Educ Book. 2014:51-9
» PubMed
2013 / 10.1371/journal.pone.0063933
Hoepner S, Loh JM, Riccadonna C, Derouazi M, Maroun CY, Dietrich PY, Walker PR. Synergy between CD8 T cells and Th1 or Th2 polarised CD4 T cells for adoptive immunotherapy of brain tumours. PLoS One. 2013 May 23;8(5):e63933
» PubMed
Hoepner S, Walker PR. Getting by with a little help from the right CD4+ T cells. Oncoimmunology. 2013 Sep 1;2(9):e25772
» PubMed
2013 / 10.1186/1742-2094-10-154
Benkhoucha M, Molnarfi N, Schneiter G, Walker PR, Lalive PH. The neurotrophic hepatocyte growth factor attenuates CD8+ cytotoxic T-lymphocyte activity. J Neuroinflammation. 2013 Dec 17;10:154
» PubMed
2013 / 10.2217/imt.13.115
Migliorini D, Dietrich PY, Walker PR. Maximizing output from current glioma vaccine trials to construct robust next-generation immunotherapies. Immunotherapy. 2013 Nov;5(11):1147-50
» PubMed
Riccadonna C, Walker PR. Macrophages and Microglia in Brain Malignancies. Tumor Microenvironment and Myelomonocytic Cells (2012)
» PubMed
2012 / 10.1093/brain/aws042
Dutoit V, Herold-Mende C, Hilf N, Schoor O, Beckhove P, Bucher J, Dorsch K, Flohr S, Fritsche J, Lewandrowski P, Lohr J, Rammensee HG, Stevanovic S, Trautwein C, Vass V, Walter S, Walker PR, Weinschenk T, Singh-Jasuja H, Dietrich PY. Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. Brain. 2012 Apr;135(Pt 4):1042-54
» PubMed
2010 / 10.1002/glia.20941
Tenan M, Aurrand-Lions M, Widmer V, Alimenti A, Burkhardt K, Lazeyras F, Belkouch MC, Hammel P, Walker PR, Duchosal MA, Imhof BA, Dietrich PY. Cooperative expression of junctional adhesion molecule-C and -B supports growth and invasion of glioma. Glia. 2010 Apr;58(5):524-37
» PubMed
2010 / 10.1158/0008-5472.CAN-09-3074
Tran Thang NN, Derouazi M, Philippin G, Arcidiaco S, Di Berardino-Besson W, Masson F, Hoepner S, Riccadonna C, Burkhardt K, Guha A, Dietrich PY, Walker PR. Immune infiltration of spontaneous mouse astrocytomas is dominated by immunosuppressive cells from early stages of tumor development. Cancer Res. 2010 Jun 15;70(12):4829-39
» PubMed
2010 / 10.1097/CCO.0b013e32833dead8
Dietrich PY, Dutoit V, Tran Thang NN, Walker PR. T-cell immunotherapy for malignant glioma: toward a combined approach. Curr Opin Oncol. 2010 Nov;22(6):604-10
» PubMed
Walker PR, Prins RM, Dietrich PY, Liau LM. Harnessing T-cell immunity to target brain tumors. CNS Cancer, Models, Prognostic Factors and Targets and Therapeutic Approaches (2009). E. G. Van Meir (Editor). New York: Humana Press. p.1165-218
» PubMed
2008 / 10.1002/glia.20715
Calzascia T, Loh JM, Di Berardino-Besson W, Masson F, Guillaume P, Burkhardt K, Herrera PL, Dietrich PY, Walker PR. Peripheral tolerance limits CNS accumulation of CD8 T cells specific for an antigen shared by tumor cells and normal astrocytes. Glia. 2008 Nov 15;56(15):1625-36
» PubMed
Sasaki K, Zhu X, Vasquez C, Nishimura F, Dusak JE, Huang J, Fujita M, Wesa A, Potter DM, Walker PR, Storkus WJ, Okada H. Preferential expression of very late antigen-4 on type 1 CTL cells plays a critical role in trafficking into central nervous system tumors. Cancer Res. 2007 Jul 1;67(13):6451-8
» PubMed
Masson F, Calzascia T, Di Berardino-Besson W, de Tribolet N, Dietrich PY, Walker PR. Brain microenvironment promotes the final functional maturation of tumor-specific effector CD8+ T cells. J Immunol. 2007 Jul 15;179(2):845-53
» PubMed
Zhu X, Nishimura F, Sasaki K, Fujita M, Dusak JE, Eguchi J, Fellows-Mayle W, Storkus WJ, Walker PR, Salazar AM, Okada H. Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models. J Transl Med. 2007 Feb 12;5:10
» PubMed