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Immunobiology of brain tumours.

The dialogue between cancer and the immune response is complex and can have unique features according to the site of growth of a solid tumour. Our group focuses on brain tumours, particularly gliomas, and their interaction with spontaneous and induced immune responses.
We are intensively investigating a novel tumour vaccine that is based on antigenic proteins coupled to a cell penetrating peptide (CPP) that is efficiently delivered to antigen presenting cells. This leads to efficient processing and presentation of antigenic peptides to both CD4 and CD8 T cells. To have therapeutic impact, vaccine-induced T cells much reach the tumour and function in the tumour bed. We have identified markers and mechanisms by which T cells are programmed to efficiently traffic to a brain tumour; the optimal vaccine will exploit these properties. Stimulation of protective CD4 T cells is as important as stimulating CD8 cytotoxic T cells. In mouse brain tumour models (and in human glioma), the balance is towards regulatory CD4 T cells and an immunosuppressive tumour microenvironment, whereas transfer of Th1 polarised CD4 T cells can promote CD8 T cell recruitment and type 1 cytokine secretion.
Ultimately, the immune cells that impact on tumour growth must function in the hostile tumour bed that often has a low oxygen tension; we are therefore exploring immune function under hypoxia to better understand this tumour microenvironment.
Finally, clinical translation of cancer immunotherapy will generally require compatibility with other treatments previously or concomitantly given to patients. Our research objective is to identify chemotherapies that can synergise with immunotherapy to target even glioma stem-like cells that are refractory to current treatment modalities.

Group's publications

Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy.
BRAIN
2012 vol. 135(Pt 4) pp. 1042-1054
DUTOIT V AND AL.

Immune infiltration of spontaneous mouse astrocytomas is dominated by immunosuppressive cells from early stages of tumor development.
CANCER RESEARCH
2010 vol. 70(12) pp. 4829-4839
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

T-cell immunotherapy for malignant glioma: toward a combined approach.
CURRENT OPINION IN ONCOLOGY
2010 vol. 22(6) pp. 604-610
DIETRICH PY, TRAN THANG NN, DUTOIT V, WALKER PR

Cooperative expression of junctional adhesion molecule-C and -B supports growth and invasion of glioma.
GLIA
2010 vol. 58(5) pp. 524-537
TENAN M, AURRAND-LIONS M, WIDMER V, ALIMENTI A., BURKHARDT K, LAZEYRAS F, BELKOUCH MC, HAMMEL P, WALKER PR, DUCHOSAL MA, IMHOF B, DIETRICH PY

Peripheral tolerance limits CNS accumulation of CD8 T cells specific for an antigen shared by tumor cells and normal astrocytes.
GLIA
2008 vol. 56(15) pp. 1625-1636
CALZASCIA T, LOH JM, DI BERARDINO-BESSON W, MASSON F, GUILLAUME P, BURKHARDT K, HERRERA PL, DIETRICH PY, WALKER PR

Preferential expression of very late antigen-4 on type 1 CTL cells plays a critical role in trafficking into central nervous system tumors
CANCER RESEARCH
2007 vol. 67(13) pp. 6451-6458
SASAKI K, ZHU XM, VASQUEZ C, NISHIMURA F, DUSAK JE, HUANG J, FUJITA M, WESA A, POTTER DM, WALKER PR, STORKUS WJ, OKADA H

Brain microenvironment promotes the final functional maturation of tumor-specific effector CD8(+) T cells
JOURNAL OF IMMUNOLOGY
2007 vol. 179 pp. 845-853
MASSON F, CALZASCIA T, DI BERARDINO-BESSON, W, DE TRIBOLET N, DIETRICH PY, WALKER PR

Tissue homing and persistence of defined antigen-specific CD8(+) tumor-reactive T-cell clones in long-term melanoma survivors
JOURNAL OF INVESTIGATIVE DERMATOLOGY
2007 vol. 127 pp. 622-629
LE GAL FA, WIDMER VM, DUTOIT V, RUBIO-GODOY V, SCHRENZEL J, WALKER PR, ROMERO PJ, VALMORI D, SPEISER DE, DIETRICH PY

Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models.
JOURNAL OF TRANSLATIONAL MEDICINE
2007 vol. 5 pp. 10-10
ZHU X, NISHIMURA F, SASAKI K, FUJITA M, DUSAK JE, EGUCHI J, FELLOWS-MAYLE W, STORKUS WJ, WALKER PR, SALAZAR AM, OKADA H

Homing phenotypes of tumor-specific CD8 T cells are predetermined at the tumor site by crosspresenting APCs
IMMUNITY
2005 vol. 22 pp. 175-184
CALZASCIA THOMAS, MASSON FREDERIC, DI BERARDINO-BESSON WILMA, CONTASSOT EMMANUEL, WILMOTTE RICK, AURRAND-LIONS MICHEL, RÜEGG CURZIO, DIETRICH PIERRE-YVES, WALKER PAUL

B7-homolog I expression by human glioma: a new mechanism of immune evasion
NEUROREPORT
2005 vol. 16 pp. 1081-1085
WILMOTTE RICK, BURKHARDT KARIM, KINDLER VINCENT, BELKOUCH MARIE-CLAUDE, DUSSEX GERALDINE, DE TRIBOLET NICOLAS, WALKER PAUL, DIETRICH PIERRE-YVES

Lentiviral Transduction of Dendritic Cells Confers Protective Antiviral Immunity in vivo
JOURNAL OF VIROLOGY
2004 vol. 78 pp. 7843-7845
ZAREI SHOHREH, ABRAHAM SHAHNAZ, ARRIGHI JEAN-FRANCOIS, HALLER OLIVIER, CALZASCIA THOMAS, WALKER PAUL, KUNDIG TM, HAUSER CONRAD, PIGUET VINCENT

T-cell immune responses in the brain and their relevance for cerebral malignancies
BRAIN RESEARCH REVIEWS
2003 vol. 42(2) pp. 97-122
WALKER PR, CALZASCIA T, DE TRIBOLET N, DIETRICH PY

Cutting edge: cross-presentation as a mechanism for efficient recruitment of tumor-specific CTL to the brain
JOURNAL OF IMMUNOLOGY
2003 vol. 171(5) pp. 2187-2191
CALZASCIA T, DI BERARDINO-BESSON W, WILMOTTE R, MASSON F, DE TRIBOLET N, DIETRICH PY, WALKER PR

Prevalent role of TCR alpha-chain in the selection of the preimmune repertoire specific for a human tumor-associated self-antigen.
JOURNAL OF IMMUNOLOGY
2003 vol. pp. 5103-5109
DIETRICH PY, LE GAL FA, DUTOIT V, PITTET MJ, TRAUTMAN L, ZIPPELIUS A, COGNET I, WIDMER V, WALKER PR, MICHIELIN O, GUILLAUME P, CONNEROTTE T, JOTEREAU F, COULIE PG, ROMERO P, CEROTTINI JC, BONNEVILLE M, VALMORI D

Efficient Induction of CD8 T-Associated Immune Protection by Vaccination with mRNA Transfected Dendritic Cells
JOURNAL OF INVESTIGATIVE DERMATOLOGY
2003 vol. 121 pp. 745-750
ZAREI S, ARRIGHI JF, ONGARO G, CALZASCIA T, HALLER O, FROSSARD C, PIGUET V, WALKER PR, HAUSER C

Death receptors on reactive astrocytes : a key role in the fine tuning of brain inflammation
NEUROLOGY
2003 vol. 60(4) pp. 548-554
DIETRICH PY, WALKER PR, SAAS P

All in the head: obstacles for immune rejection of brain tumours
IMMUNOLOGY
2002 vol. 107 pp. 28-38
WALKER PR, CALZASCIA T, DIETRICH PY

Sister cytotoxic CD8+ T cell clones differing in natural killer inhibitory receptor expression in human astrocytoma
IMMUNOLOGY LETTERS
2002 vol. 81 pp. 125-132
PERRIN G, SPEISER D, PORRET A, QUIQUEREZ AL, WALKER PR, DIETRICH PY

Vaccination with a Melan-A peptide selects an oligoclonal T cell population with increased functional avidity and tumor reactivity
JOURNAL OF IMMUNOLOGY
2002 vol. 168 pp. 4231-4240
VALMORI D, DUTOIT V, QUIQUEREZ AL, PITTET MJ, GUILLAUME P, RUBIO-GOGOY V, WALKER PR, RIMOLDI D, LIENARD D, CEROTTINI JC, ROMERO P, DIETRICH PY

A self-defence mechanism of astrocytes against Fas-mediated death involving interleukin-8 and CXCR2
NEUROREPORT
2002 vol. 13 pp. 1921-1924
SAAS P, WALKER PR, QUIQUEREZ AL, CHALMERS DE, ARRIGHI JF, LIENARD A, BOUCRAUT J, DIETRICH PY

Research's domains




DATABASE-RESEARCH	GROUP OF CLINICAL BIOLOGY RESEARCH

Walker Paul Richard	Head of group CV	Research subject	Members of the group


	Links about the group Dr. P. WALKER HUG/Spécialités de Médecine Service d'oncologie Rue Gabrielle-Perret-Gentil 4 1211 Genève 14 Suisse Paul.Walker@hcuge.ch Tel.: +41 22 37 29 880 Comments Pages updated the 17.11.2015		Reseach's subject \| Group's publications \| Research's domains Immunobiology of brain tumours. The dialogue between cancer and the immune response is complex and can have unique features according to the site of growth of a solid tumour. Our group focuses on brain tumours, particularly gliomas, and their interaction with spontaneous and induced immune responses. We are intensively investigating a novel tumour vaccine that is based on antigenic proteins coupled to a cell penetrating peptide (CPP) that is efficiently delivered to antigen presenting cells. This leads to efficient processing and presentation of antigenic peptides to both CD4 and CD8 T cells. To have therapeutic impact, vaccine-induced T cells much reach the tumour and function in the tumour bed. We have identified markers and mechanisms by which T cells are programmed to efficiently traffic to a brain tumour; the optimal vaccine will exploit these properties. Stimulation of protective CD4 T cells is as important as stimulating CD8 cytotoxic T cells. In mouse brain tumour models (and in human glioma), the balance is towards regulatory CD4 T cells and an immunosuppressive tumour microenvironment, whereas transfer of Th1 polarised CD4 T cells can promote CD8 T cell recruitment and type 1 cytokine secretion. Ultimately, the immune cells that impact on tumour growth must function in the hostile tumour bed that often has a low oxygen tension; we are therefore exploring immune function under hypoxia to better understand this tumour microenvironment. Finally, clinical translation of cancer immunotherapy will generally require compatibility with other treatments previously or concomitantly given to patients. Our research objective is to identify chemotherapies that can synergise with immunotherapy to target even glioma stem-like cells that are refractory to current treatment modalities. Group's publications Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy. BRAIN 2012 vol. 135(Pt 4) pp. 1042-1054 DUTOIT V AND AL. Immune infiltration of spontaneous mouse astrocytomas is dominated by immunosuppressive cells from early stages of tumor development. CANCER RESEARCH 2010 vol. 70(12) pp. 4829-4839 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 T-cell immunotherapy for malignant glioma: toward a combined approach. CURRENT OPINION IN ONCOLOGY 2010 vol. 22(6) pp. 604-610 DIETRICH PY, TRAN THANG NN, DUTOIT V, WALKER PR Cooperative expression of junctional adhesion molecule-C and -B supports growth and invasion of glioma. GLIA 2010 vol. 58(5) pp. 524-537 TENAN M, AURRAND-LIONS M, WIDMER V, ALIMENTI A., BURKHARDT K, LAZEYRAS F, BELKOUCH MC, HAMMEL P, WALKER PR, DUCHOSAL MA, IMHOF B, DIETRICH PY Peripheral tolerance limits CNS accumulation of CD8 T cells specific for an antigen shared by tumor cells and normal astrocytes. GLIA 2008 vol. 56(15) pp. 1625-1636 CALZASCIA T, LOH JM, DI BERARDINO-BESSON W, MASSON F, GUILLAUME P, BURKHARDT K, HERRERA PL, DIETRICH PY, WALKER PR Preferential expression of very late antigen-4 on type 1 CTL cells plays a critical role in trafficking into central nervous system tumors CANCER RESEARCH 2007 vol. 67(13) pp. 6451-6458 SASAKI K, ZHU XM, VASQUEZ C, NISHIMURA F, DUSAK JE, HUANG J, FUJITA M, WESA A, POTTER DM, WALKER PR, STORKUS WJ, OKADA H Brain microenvironment promotes the final functional maturation of tumor-specific effector CD8(+) T cells JOURNAL OF IMMUNOLOGY 2007 vol. 179 pp. 845-853 MASSON F, CALZASCIA T, DI BERARDINO-BESSON, W, DE TRIBOLET N, DIETRICH PY, WALKER PR Tissue homing and persistence of defined antigen-specific CD8(+) tumor-reactive T-cell clones in long-term melanoma survivors JOURNAL OF INVESTIGATIVE DERMATOLOGY 2007 vol. 127 pp. 622-629 LE GAL FA, WIDMER VM, DUTOIT V, RUBIO-GODOY V, SCHRENZEL J, WALKER PR, ROMERO PJ, VALMORI D, SPEISER DE, DIETRICH PY Toll like receptor-3 ligand poly-ICLC promotes the efficacy of peripheral vaccinations with tumor antigen-derived peptide epitopes in murine CNS tumor models. JOURNAL OF TRANSLATIONAL MEDICINE 2007 vol. 5 pp. 10-10 ZHU X, NISHIMURA F, SASAKI K, FUJITA M, DUSAK JE, EGUCHI J, FELLOWS-MAYLE W, STORKUS WJ, WALKER PR, SALAZAR AM, OKADA H Homing phenotypes of tumor-specific CD8 T cells are predetermined at the tumor site by crosspresenting APCs IMMUNITY 2005 vol. 22 pp. 175-184 CALZASCIA THOMAS, MASSON FREDERIC, DI BERARDINO-BESSON WILMA, CONTASSOT EMMANUEL, WILMOTTE RICK, AURRAND-LIONS MICHEL, RÜEGG CURZIO, DIETRICH PIERRE-YVES, WALKER PAUL B7-homolog I expression by human glioma: a new mechanism of immune evasion NEUROREPORT 2005 vol. 16 pp. 1081-1085 WILMOTTE RICK, BURKHARDT KARIM, KINDLER VINCENT, BELKOUCH MARIE-CLAUDE, DUSSEX GERALDINE, DE TRIBOLET NICOLAS, WALKER PAUL, DIETRICH PIERRE-YVES Lentiviral Transduction of Dendritic Cells Confers Protective Antiviral Immunity in vivo JOURNAL OF VIROLOGY 2004 vol. 78 pp. 7843-7845 ZAREI SHOHREH, ABRAHAM SHAHNAZ, ARRIGHI JEAN-FRANCOIS, HALLER OLIVIER, CALZASCIA THOMAS, WALKER PAUL, KUNDIG TM, HAUSER CONRAD, PIGUET VINCENT T-cell immune responses in the brain and their relevance for cerebral malignancies BRAIN RESEARCH REVIEWS 2003 vol. 42(2) pp. 97-122 WALKER PR, CALZASCIA T, DE TRIBOLET N, DIETRICH PY Cutting edge: cross-presentation as a mechanism for efficient recruitment of tumor-specific CTL to the brain JOURNAL OF IMMUNOLOGY 2003 vol. 171(5) pp. 2187-2191 CALZASCIA T, DI BERARDINO-BESSON W, WILMOTTE R, MASSON F, DE TRIBOLET N, DIETRICH PY, WALKER PR Prevalent role of TCR alpha-chain in the selection of the preimmune repertoire specific for a human tumor-associated self-antigen. JOURNAL OF IMMUNOLOGY 2003 vol. pp. 5103-5109 DIETRICH PY, LE GAL FA, DUTOIT V, PITTET MJ, TRAUTMAN L, ZIPPELIUS A, COGNET I, WIDMER V, WALKER PR, MICHIELIN O, GUILLAUME P, CONNEROTTE T, JOTEREAU F, COULIE PG, ROMERO P, CEROTTINI JC, BONNEVILLE M, VALMORI D Efficient Induction of CD8 T-Associated Immune Protection by Vaccination with mRNA Transfected Dendritic Cells JOURNAL OF INVESTIGATIVE DERMATOLOGY 2003 vol. 121 pp. 745-750 ZAREI S, ARRIGHI JF, ONGARO G, CALZASCIA T, HALLER O, FROSSARD C, PIGUET V, WALKER PR, HAUSER C Death receptors on reactive astrocytes : a key role in the fine tuning of brain inflammation NEUROLOGY 2003 vol. 60(4) pp. 548-554 DIETRICH PY, WALKER PR, SAAS P All in the head: obstacles for immune rejection of brain tumours IMMUNOLOGY 2002 vol. 107 pp. 28-38 WALKER PR, CALZASCIA T, DIETRICH PY Sister cytotoxic CD8+ T cell clones differing in natural killer inhibitory receptor expression in human astrocytoma IMMUNOLOGY LETTERS 2002 vol. 81 pp. 125-132 PERRIN G, SPEISER D, PORRET A, QUIQUEREZ AL, WALKER PR, DIETRICH PY Vaccination with a Melan-A peptide selects an oligoclonal T cell population with increased functional avidity and tumor reactivity JOURNAL OF IMMUNOLOGY 2002 vol. 168 pp. 4231-4240 VALMORI D, DUTOIT V, QUIQUEREZ AL, PITTET MJ, GUILLAUME P, RUBIO-GOGOY V, WALKER PR, RIMOLDI D, LIENARD D, CEROTTINI JC, ROMERO P, DIETRICH PY A self-defence mechanism of astrocytes against Fas-mediated death involving interleukin-8 and CXCR2 NEUROREPORT 2002 vol. 13 pp. 1921-1924 SAAS P, WALKER PR, QUIQUEREZ AL, CHALMERS DE, ARRIGHI JF, LIENARD A, BOUCRAUT J, DIETRICH PY Research's domains