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1. Resident Memory T Cells as Surrogate Markers of the Efficacy of Cancer Vaccines

Author

Hélène Roussel, Eric Tartour, and Mevyn Nizard

Subjects
0301 basic medicine, Cancer Research, CD8-Positive T-Lymphocytes, Cancer Vaccines, Article, 03 medical and health sciences, Neoplasms, Tumor regression, Medicine, Humans, Intramuscular route, business.industry, Cancer, medicine.disease, 030104 developmental biology, Oncology, Immunization, Genital tract, Immunology, Cancer vaccine, business, Immunologic memory, Immunologic Memory, CD8, Biomarkers
Abstract

Cancer vaccine boost via the cervicovaginal rather than the intramuscular route of immunization appears to be crucial to induce genital CD8+ T cells and tumor regression. This clinical activity is correlated with the ability of the mucosal boost to elicit resident memory T cells in the genital tract. Clin Cancer Res; 22(3); 530–2. ©2015 AACR. See related article by Sun et al., p. 657

Published
2015

2. Combinaison of an anti HPV-E7 vaccine to radiotherapy: preclinical data in a head and neck model

Author

C. Badoual, D. Helley, E. Dransart, Jean-Luc Perfettini, Delphine Dugue, Michele Mondini, C. Clémenson, Mauro Loi, Thi Thuy Hien Tran, E. Louvet, Mevyn Nizard, L. Mauge, E. Tartour, Marie-Catherine Vozenin, L. Johannes, Pierre Maroun, Eric Deutsch, and Julien Adam

Subjects
Oncology, medicine.medical_specialty, business.industry, medicine.medical_treatment, Hematology, Preclinical data, Radiation therapy, Radiology Nuclear Medicine and imaging, Internal medicine, medicine, Radiology, Nuclear Medicine and imaging, business, Head and neck
Published
2016
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3. Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer

Author

Dominique Helley, Estelle Dransart, Jean-Luc Perfettini, Mevyn Nizard, Delphine Dugue, Pierre Maroun, Mauro Loi, Julien Adam, Thi Tran, Eric Tartour, Eric Deutsch, Marie-Catherine Vozenin, Céline Clémenson, Michele Mondini, Ludger Johannes, Cécile Badoual, Laetitia Mauge, and Emilie Louvet

Subjects
Cancer Research, Combination therapy, medicine.medical_treatment, Fluorescent Antibody Technique, CD8-Positive T-Lymphocytes, Shiga Toxins, Cancer Vaccines, Cell Line, Immune system, medicine, Animals, Papillomavirus Vaccines, Antigens, Radiotherapy, business.industry, Head and neck cancer, Papillomavirus Infections, Vaccination, Muscle, Smooth, Immunotherapy, medicine.disease, Flow Cytometry, Intercellular Adhesion Molecule-1, Head and neck squamous-cell carcinoma, Combined Modality Therapy, Actins, Radiation therapy, Mice, Inbred C57BL, Oncology, Head and Neck Neoplasms, Immunology, Cancer research, Female, Proteoglycans, Cancer vaccine, business, Pericytes
Abstract

There is growing interest in the association of radiotherapy and immunotherapy for the treatment of solid tumors. Here, we report an extremely effective combination of local irradiation (IR) and Shiga Toxin B (STxB)–based human papillomavirus (HPV) vaccination for the treatment of HPV-associated head and neck squamous cell carcinoma (HNSCC). The efficacy of the irradiation and vaccine association was tested using a model of HNSCC obtained by grafting TC-1/luciferase cells at a submucosal site of the inner lip of immunocompetent mice. Irradiation and the STxB-E7 vaccine acted synergistically with both single and fractionated irradiation schemes, resulting in complete tumor clearance in the majority of the treated mice. A dose threshold of 7.5 Gy was required to elicit the dramatic antitumor response. The combined treatment induced high levels of tumor-infiltrating, antigen-specific CD8+ T cells, which were required to trigger the antitumor activity. Treatment with STxB-E7 and irradiation induced CD8+ T-cell memory, which was sufficient to exert complete antitumor responses in both local recurrences and distant metastases. We also report for the first time that a combination therapy based on local irradiation and vaccination induces an increased pericyte coverage (as shown by αSMA and NG2 staining) and ICAM-1 expression on vessels. This was associated with enhanced intratumor vascular permeability that correlated with the antitumor response, suggesting that the combination therapy could also act through an increased accessibility for immune cells. The combination strategy proposed here offers a promising approach that could potentially be transferred into early-phase clinical trials. Mol Cancer Ther; 14(6); 1336–45. ©2015 AACR.

Published
2014

4. A Correction to the Research Article Titled: 'Mucosal Imprinting of Vaccine-Induced CD8 + T Cells Is Crucial to Inhibit the Growth of Mucosal Tumors' by F. Sandoval, M. Terme, M. Nizard, C. Badoual, M.-F. Bureau, L. Freyburger, O. Clement, E. Marcheteau, A. Gey, G. Fraisse, C. Bouguin, N. Merillon, E. Dransart, T. Tran, F. Quintin-Colonna, G. Autret, M. Thiebaud, M. Suleman, S. Riffault, T.-C. Wu, O. Launay, C. Danel, J. Taieb, J. Richardson, L. Zitvogel, W. H. Fridman, L. Johannes, E. Tartour

Author

Wolf H. Fridman, Julien Taieb, Federico Sandoval, Laurence Zitvogel, Magali Terme, Sabine Riffault, G. Fraisse, Françoise Quintin-Colonna, Gwennhael Autret, C. Bouguin, Eric Tartour, T. C. Wu, Olivier Clément, Elie Marcheteau, Thi Tran, Alain Gey, M. Suleman, Claire Danel, Michel Bureau, Jennifer Richardson, Ludovic Freyburger, Marine Thiebaud, Estelle Dransart, Mevyn Nizard, Odile Launay, Ludger Johannes, Cécile Badoual, and Nathalie Merillon

Subjects
business.industry, Translational medicine, Cytotoxic T cell, Medicine, General Medicine, business, Imprinting (organizational theory), Cell biology
Published
2013
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5. Immunotherapy of HPV-associated head and neck cancer: critical parameters

Author

Nadine Benhamouda, Mevyn Nizard, Clémence Granier, Hélène Péré, Daniel Brasnu, Stéphane Hans, Eric Tartour, Magali Terme, Cécile Badoual, Federico Sandoval, Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires (LRI - EA4062), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d'anatomo-pathologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Laboratoire de Virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'oto-rhino-laryngologie et chirurgie cervico-faciale [CHU HEGP], LPP - Laboratoire de Phonétique et Phonologie - UMR 7018 (LPP), Université Sorbonne Nouvelle - Paris 3-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Cytokines et Immunologie des Tumeurs Humaines (U753), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires ( LRI - EA4062 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], LPP - Laboratoire de Phonétique et Phonologie - UMR 7018 ( LPP ), Université Sorbonne Nouvelle - Paris 3-Centre National de la Recherche Scientifique ( CNRS ), Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Cytokines et Immunologie des Tumeurs Humaines ( U753 ), and Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM )

Subjects
HPV, medicine.medical_treatment, Immunology, head and neck, Downregulation and upregulation, MHC class I, medicine, Immunology and Allergy, Clinical efficacy, Human papillomavirus, [SHS.LANGUE]Humanities and Social Sciences/Linguistics, Head and neck, Mucosal immunity, ComputingMilieux_MISCELLANEOUS, biology, business.industry, Head and neck cancer, virus diseases, Immunotherapy, medicine.disease, female genital diseases and pregnancy complications, PD1, Oncology, [ SHS.LANGUE ] Humanities and Social Sciences/Linguistics, biology.protein, Cancer research, mucosal immunity, immunotherapy, business
Abstract

Various arguments support the development of a vaccine targeting human papillomavirus (HPV) for the treatment of HPV-associated head and neck cancer. However, the mucosal localization of this tumor, the HPV-driven downregulation of MHC Class I molecules and various other immunosuppressive mechanisms must be carefully considered to improve the clinical efficacy of such an immunotherapeutic strategy.

Published
2013

6. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer

Author

Rinat Rotem-Yehudar, Patrick Bruneval, Cécile Alanio, Daniel Olive, Emeline Levionnois, Françoise Quintin-Colonna, Mevyn Nizard, Thi Tran, Wolf H. Fridman, Nathalie Merillon, Cordelia Van Ryswick, Hélène Péré, Coralie L. Guerin, François M. Lemoine, Alain Gey, Ludger Johannes, Cécile Badoual, Federico Sandoval, Ali Si-Mohamed, Eric Tartour, Nadine Benhamouda, Estelle Dransart, Stéphane Oudard, Nicolas Besnier, Stéphane Hans, Daniel Brasnu, Béatrix Barry, Patrice Ravel, Sebastien Albert, and Anne Chauvat

Subjects
Oncology, Cancer Research, medicine.medical_specialty, T-Lymphocytes, Programmed Cell Death 1 Receptor, Fluorescent Antibody Technique, Lymphocyte Activation, Flow cytometry, Mice, Immune system, Lymphocytes, Tumor-Infiltrating, T-Lymphocyte Subsets, Internal medicine, medicine, Carcinoma, Biomarkers, Tumor, Tumor Microenvironment, Animals, Humans, medicine.diagnostic_test, business.industry, Head and neck cancer, Papillomavirus Infections, Cancer, FOXP3, medicine.disease, Flow Cytometry, Prognosis, Blockade, Mice, Inbred C57BL, Head and Neck Neoplasms, Carcinoma, Squamous Cell, Female, Cancer vaccine, business
Abstract

Head and neck cancers positive for human papillomavirus (HPV) have a more favorable clinical outcome than HPV-negative cancers, but it is unknown why this is the case. We hypothesized that prognosis was affected by intrinsic features of HPV-infected tumor cells or differences in host immune response. In this study, we focused on a comparison of regulatory Foxp3+ T cells and programmed death-1 (PD-1)+ T cells in the microenvironment of tumors that were positive or negative for HPV, in two groups that were matched for various clinical and biologic parameters. HPV-positive head and neck cancers were more heavily infiltrated by regulatory T cells and PD-1+ T cells and the levels of PD-1+ cells were positively correlated with a favorable clinical outcome. In explaining this paradoxical result, we showed that these PD-1+ T cells expressed activation markers and were functional after blockade of the PD-1–PD-L1 axis in vitro. Approximately 50% of PD-1+ tumor-infiltrating T cells lacked Tim-3 expression and may indeed represent activated T cells. In mice, administration of a cancer vaccine increased PD-1 on T cells with concomitant tumor regression. In this setting, PD-1 blockade synergized with vaccine in eliciting antitumor efficacy. Our findings prompt a need to revisit the significance of PD-1–infiltrating T cells in cancer, where we suggest that PD-1 detection may reflect a previous immune response against tumors that might be reactivated by PD-1/PD-L1 blockade. Cancer Res; 73(1); 128–38. ©2012 AACR.

Published
2012

7. Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer

Author

Françoise Quintin-Colonna, Claire Banissi, Hélène Péré, Olivier Adotevi, Magali Terme, Julien Taieb, Nathalie Merillon, Mevyn Nizard, Jagadeesh Bayry, Ve´ronique Quillien, Ste´phane Oudard, Eric Tartour, Alain Carpentier, Wolf H. Fridman, Cécile Badoual, Corinne Tanchot, Elie Marcheteau, Federico Sandoval, Laurence Zitvogel, Guido Kroemer, Laboratoire de Virologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Paris-Centre de Recherche Cardiovasculaire (PARCC - UMR-S U970), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Paris Descartes - Paris 5 (UPD5)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Role des Cellules Dendritiques Dans la Regulation des Effecteurs de l'Immunite Antitumorale, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'hépatogastro-entérologie et d'oncologie digestive, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Service d'anatomo-pathologie [CHU HEGP], Service d'Oncologie Médicale [CHRU Besançon], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) (RIGHT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté]), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Service de Biologie, CRLCC Eugène Marquis (CRLCC), École nationale vétérinaire d'Alfort (ENVA), Université Paris Descartes - Faculté de Médecine (UPD5 Médecine), Université Paris Descartes - Paris 5 (UPD5), Apoptose, cancer et immunité (U848), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Plateforme de métabolomique, Direction de la recherche [Gustave Roussy], Institut Gustave Roussy (IGR)-Institut Gustave Roussy (IGR), Pôle de biologie, Laboratoire d'Immunologie Cellulaire et Clinique, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR58-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre d'Investigation Clinique en Biotherapie des cancers (CIC 1428 , CBT 507 ), Institut Gustave Roussy (IGR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Immunologie des tumeurs et immunothérapie (UMR 1015), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Gustave Roussy (IGR)-Université Paris-Sud - Paris 11 (UP11), School of Medicine, Université Paris-Sud - Paris 11 (UP11), Service d'oncologie médicale [CHU HEGP], Jonchère, Laurent, Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Université de Franche-Comté (UFC), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), École nationale vétérinaire - Alfort (ENVA), Institut Gustave Roussy (IGR)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Université Sorbonne Paris Cité (USPC), Institut National de la Santé et de la Recherche Médicale (INSERM), Service de gastroenterologie [CHU HEGP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Structures et Marché Agricoles, Ressources et Territoires (SMART), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, Laboratoire de Recherche en Imagerie : Méthodes d'imagerie des Échanges transcapillaires (LRI - EA4062), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Apoptose, cancer et immunité (Equipe labellisée Ligue contre le cancer - CRC - Inserm U1138), Institut Gustave Roussy (IGR)-Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Gustave Roussy (IGR), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), AGROCAMPUS OUEST, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut National de la Recherche Agronomique (INRA), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Paris-Centre de Recherche Cardiovasculaire ( PARCC - U970 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Centre de Recherche des Cordeliers ( CRC (UMR_S 872) ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Européen Georges Pompidou [APHP] ( HEGP ), Service d'oncologie Médicale, Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ) -Hôpital Jean Minjoz, Interactions hôte-greffon-tumeur, ingénierie cellulaire et génique - UFC (UMR INSERM 1098) ( HOTE GREFFON ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Etablissement français du sang [Bourgogne-France-Comté] ( EFS [Bourgogne-France-Comté] ) -Université de Franche-Comté ( UFC ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), CRLCC Eugène Marquis ( CRLCC ), École nationale vétérinaire d'Alfort ( ENVA ), Université Paris Descartes - Faculté de Médecine ( UPD5 Médecine ), Université Paris Descartes - Paris 5 ( UPD5 ), Apoptose, cancer et immunité ( U848 ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Institut Gustave Roussy ( IGR ) -Institut Gustave Roussy ( IGR ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -IFR58-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'Investigation Clinique en Biotherapie des cancers ( CIC 1428 , CBT 507 ), Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Immunologie des tumeurs et immunothérapie ( UMR 1015 ), Université Paris-Sud - Paris 11 ( UP11 ), Université Paris Descartes - Paris 5 (UPD5)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS BFC)-Université de Franche-Comté (UFC)

Subjects
Chemokine, regulatory T cell, Regulatory T cell, T cell, Immunology, Population, chemical and pharmacologic phenomena, Review, [SDV.GEN] Life Sciences [q-bio]/Genetics, [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity, 03 medical and health sciences, 0302 clinical medicine, medicine, antiangiogenic molecule, Immunology and Allergy, IL-2 receptor, [SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology, education, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Tumor microenvironment, education.field_of_study, [SDV.GEN]Life Sciences [q-bio]/Genetics, biology, business.industry, chemokine, FOXP3, hemic and immune systems, 3. Good health, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, biology.protein, CCR4, business, [ SDV.GEN ] Life Sciences [q-bio]/Genetics, Tyrosine kinase
Abstract

International audience; CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) have emerged as a dominant T cell population inhibiting anti-tumor effector T cells. Initial strategies used for Treg-depletion (cyclophosphamide, anti-CD25 mAb ...) also targeted activated T cells, as they share many phenotypic markers. Current, ameliorated approaches to inhibit Treg aim to either block their function or their migration to lymph nodes and the tumor microenvironment. Various drugs originally developed for other therapeutic indications (anti-angiogenic molecules, tyrosine kinase inhibitors, etc) have recently been discovered to inhibit Treg. These approaches are expected to be rapidly translated to clinical applications for therapeutic use in combination with immunomodulators.

Published
2012
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8. Abstract 2830: Mucosal imprinting of vaccine induced-CD8+T cells is crucial to inhibit mucosal tumors

Author

Wolf H. Fridman, Françoise Quintin-Colonna, Michel-Francis Bureau, Estelle Dransart, Federico Sandoval, Magali Terme, Alain Gey, Eric Tartour, Tzyy Choou Wu, Mevyn Nizard, Ludger Johannes, Cécile Badoual, Gwenhael Autret, Elie Marcheteau, and Olivier Clément

Subjects
Cancer Research, business.industry, Spleen, Dendritic cell, medicine.disease, Vaccination, medicine.anatomical_structure, Immune system, Oncology, Immunology, Medicine, Cytotoxic T cell, Cancer vaccine, business, Lung cancer, CD8
Abstract

Although many human cancers are located in mucosal sites, most cancer vaccines are tested against subcutaneous tumors in preclinical models. The utility of preferentially inducing an anti-tumor immune response in the mucosal anatomic site of tumors has never been addressed. We therefore wondered whether mucosa-specific homing instructions to the immune system might influence mucosal tumor outgrowth. For this purpose, we set up original orthotopic models of head and neck and lung cancers monitored by magnetic resonance imaging or luciferase based in vivo optical imaging and vaccine based on a non replicative delivery system, the B subunit of Shiga toxin (STxB) as mucosal vector which has previously been shown to target antigen to dendritic cells. We showed that the growth of orthotopic head and neck or lung cancers expressing the E7 protein from HPV16 was only inhibited, when a cancer vaccine was delivered by the intranasal (i.n) mucosal and not the intramuscular (i.m) route. This anti-tumor effect was dependent on mucosal CD8+T cells as : i) Only a vaccine composed of STxB coupled to an E7 derived polypeptide (STxB-E7), but not the free E7 polypeptide elicited mucosal CD8+T cells. This mucosal induction of anti-E7 CD8+T cells, but not the systemic (spleen) specific anti-E7 CD8+T cells correlated with mucosal tumor protection. ii) A greater mucosal tumor infiltration of CD8+T cells was detected 7 days after tumor graft in mice that had been previously intranasally immunized with STxB-E7, than in mice vaccinated by the i.m. route. iii) CD8+T cell-depleted mice vaccinated with STxB-E7 by the i.n. route died before 20 days, whereas mice survived more than 6 months without CD8 depletion. As control, both routes of vaccine administration controlled the growth of subcutaneous tumors and elicited anti-E7 specific CD8+T cells in the spleen. To explain this finding, we demonstrated that only i.n. vaccination elicited mucosal specific CD8+T cells expressing the mucosal integrin CD49a. Blockade of CD49a decreased intratumoral CD8+T cell infiltration and the efficacy of cancer vaccine on mucosal tumor. We then showed that after intranasal vaccination, only dendritic cell from lung parenchyma, but not from spleen induced the expression of CD49a on co-cultured specific CD8+T cells. Tumor-infiltrating lymphocytes from human mucosal lung cancer also expressed CD49a at higher levels than TIL from non mucosal tumors, supporting the relevance and possible extrapolation of these results in humans. We thus identified a link between the route of vaccination and the induction of a mucosal homing program on induced CD8+T cells controlling their trafficking with a direct application on the efficacy of cancer vaccine to control mucosal tumors. Citation Format: Federico Sandoval, Mevyn Nizard, Magali Terme, Cecile Badoual, Michel-Francis Bureau, Olivier Clement, Elie Marcheteau, Alain Gey, Estelle Dransart, Françoise Quintin-Colonna, Gwenhael Autret, Tzyy-Choou Wu, Wolf H. Fridman, Ludger Johannes, Eric Tartour. Mucosal imprinting of vaccine induced-CD8+T cells is crucial to inhibit mucosal tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2830. doi:10.1158/1538-7445.AM2013-2830

Published
2013
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9. Abstract 5388: Local mucosal CD8+T cell response is required to inhibit the growth of orthotopic head and neck and lung cancers

Author

Ludovic Freyburger, Magali Terme, Nathalie Merillon, Estelle Dransart, Guillaume Fraisse, Françoise Quintin-Colonna, Eric Tartour, Federico Sandoval, Ludger Johannes, Olivier Clément, Cécile Badoual, Elie Marcheteau, Tzyy Choou Wu, Alain Gey, Wolf H. Fridman, Michel Bureau, and Mevyn Nizard

Subjects
Cancer Research, business.industry, T cell, Tumor antigen, Immune system, medicine.anatomical_structure, Oncology, Antigen, Immunology, Medicine, Cytotoxic T cell, Cancer vaccine, business, CD8, Tumor Graft
Abstract

Tumors may be located at mucosal or non-mucosal sites. However, the clinical benefit of preferentially inducing an anti-tumor immune response in the anatomic site of tumors has never been addressed. We set up orthotopic models of head and neck and lung cancers to compare the systemic and local anti-tumor immune response after administration of a cancer vaccine by mucosal and systemic routes. We also selected a non replicative delivery system, the B subunit of Shiga toxin (STxB), as a mucosal vector able to target dendritic cells. We show that intranasal immunization of mice with STxB based vaccine is the best route to elicit polyfunctional specific CD8+T cells in cervical and mediastinal lymph node than the use of non vectorized antigen or the intramuscular route. In line with these results, nasal mucosal administration of a model tumor antigen (E7 polypeptide from HPV 16) targeted to dendritic cells by STxB is more efficient to inhibit the growth of established orthotopic head and neck and lung cancers expressing the E7 antigen, than the administration of non vectorized antigen or the use of intramuscular route. A higher infiltration of CD8+T cells was detected 7 days after tumor graft, when mice were previously intranasally immunized with STxB-E7, than in mice vaccinated by the intramuscular route. Specific anti-E7 CD8+T cell tumor infiltration, was only observed after nasal immunization. Indeed, depletion of CD8+T cells inhibited the clinical efficiency of tumor vaccine demonstrating their role in tumor protection. In contrast, both routes completely controlled the growth of a subcutaneously E7 expressing tumor, which correlated with a similar induction of anti-E7 CD8+T cells in the spleen. Analysis of Integrin and chemokine receptor expression on tetramere positive cells showed that intranasal immunization induced higher levels of CD103 on T cells in bronchoalveolar lavage than intramuscular immunization with the same vaccine. This study emphasizes the need to elicit a potent anti-tumor response at the anatomic site of tumor and not just in the systemic compartment to induce tumor regression. This was achieved by i) administration of the vaccine by the intranasal route which was efficient in inducing CD8+T cells response at both locoregional and systemic sites allowing the control of both mucosal and non mucosal tumors. ii) The targeting of antigen to dendritic cells by STxB. This study is relevant to humans, as 30% of head and neck cancers express HPV16. Our results support the development of STxB-E7 vaccine administered by the i.n. route for the treatment of these HPV associated head and neck cancers. More generally, this study provides direct evidence for the compartmentalization of tumor immunity, a critical finding for the design of better cancer vaccines. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5388. doi:1538-7445.AM2012-5388

Published
2012
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