title: Synergy of Radiotherapy and a Cancer Vaccine for the Treatment of HPV-Associated Head and Neck Cancer.
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.
authors.affiliation: INSERM U1030 «Radiothérapie Moléculaire», Gustave Roussy Cancer Campus Grand Paris, Villejuif, France and Labex LERMIT.
authors.forename: Michele
authors.initials: M
authors.lastname: Mondini
authors.affiliation: INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.
authors.forename: Mevyn
authors.initials: M
authors.lastname: Nizard
authors.affiliation: INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.
authors.forename: Thi
authors.initials: T
authors.lastname: Tran
authors.affiliation: INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris Descartes, Sorbonne Paris-Cité, Paris, France. Service d'Hématologie Biologique, Hôpital Européen Georges-Pompidou, AP-HP, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Mauge
authors.affiliation: INSERM U1030 «Radiothérapie Moléculaire», Gustave Roussy Cancer Campus Grand Paris, Villejuif, France and Labex LERMIT. Radioterapia, Università di Firenze, Florence, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Loi
authors.affiliation: INSERM U1030 «Radiothérapie Moléculaire», Gustave Roussy Cancer Campus Grand Paris, Villejuif, France and Labex LERMIT.
authors.forename: Céline
authors.initials: C
authors.lastname: Clémenson
authors.affiliation: INSERM U1030 «Radiothérapie Moléculaire», Gustave Roussy Cancer Campus Grand Paris, Villejuif, France and Labex LERMIT.
authors.forename: Delphine
authors.initials: D
authors.lastname: Dugue
authors.affiliation: INSERM U1030 «Radiothérapie Moléculaire», Gustave Roussy Cancer Campus Grand Paris, Villejuif, France and Labex LERMIT. Département de Radiothérapie, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. Université Paris Sud, Faculté de Médecine du Kremlin-Bicêtre, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Maroun
authors.affiliation: INSERM U981, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. SIRIC SOCRATE, Villejuif Cedex, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Louvet
authors.affiliation: INSERM U981, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. SIRIC SOCRATE, Villejuif Cedex, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Adam
authors.affiliation: INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris Descartes, Sorbonne Paris-Cité, Paris, France. Service d'Anatomie Pathologique, Hôpital Européen Georges-Pompidou, AP-HP, Paris, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Badoual
authors.affiliation: INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris Descartes, Sorbonne Paris-Cité, Paris, France. Service d'Hématologie Biologique, Hôpital Européen Georges-Pompidou, AP-HP, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Helley
authors.affiliation: Institut Curie, U1143 INSERM, UMR3666 CNRS, Endocytic Trafficking and Intracellular Delivery Group, Paris, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Dransart
authors.affiliation: Institut Curie, U1143 INSERM, UMR3666 CNRS, Endocytic Trafficking and Intracellular Delivery Group, Paris, France.
authors.forename: Ludger
authors.initials: L
authors.lastname: Johannes
authors.affiliation: INSERM U1030 «Radiothérapie Moléculaire», Gustave Roussy Cancer Campus Grand Paris, Villejuif, France and Labex LERMIT. Université Paris Sud, Faculté de Médecine du Kremlin-Bicêtre, France. Laboratoire de Recherche en Radio-Oncologie, CHUV, Lausanne, Switzerland.
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Vozenin
authors.affiliation: INSERM U1030 «Radiothérapie Moléculaire», Gustave Roussy Cancer Campus Grand Paris, Villejuif, France and Labex LERMIT. Université Paris Sud, Faculté de Médecine du Kremlin-Bicêtre, France. SIRIC SOCRATE, Villejuif Cedex, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Perfettini
authors.affiliation: INSERM U970, PARCC (Paris Cardiovascular Research Center), Université Paris Descartes, Sorbonne Paris-Cité, Paris, France. Service d'Immunologie Biologique, Hôpital Européen Georges-Pompidou, AP-HP, Paris, France.
authors.forename: Eric
authors.initials: E
authors.lastname: Tartour
authors.affiliation: INSERM U1030 «Radiothérapie Moléculaire», Gustave Roussy Cancer Campus Grand Paris, Villejuif, France and Labex LERMIT. Département de Radiothérapie, Gustave Roussy Cancer Campus Grand Paris, Villejuif, France. Université Paris Sud, Faculté de Médecine du Kremlin-Bicêtre, France. SIRIC SOCRATE, Villejuif Cedex, France. eric.deutsch@gustaveroussy.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Deutsch
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000528:radiation effects; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D002460:Cell Line; D003131:Combined Modality Therapy; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006258:Head and Neck Neoplasms / Q000150:complications / Q000276:immunology / Q000628:therapy*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000737:chemistry; D030361:Papillomavirus Infections / Q000150:complications / Q000276:immunology / Q000628:therapy*; D053918:Papillomavirus Vaccines / Q000008:administration & dosage / Q000276:immunology; D020286:Pericytes / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D011509:Proteoglycans / Q000378:metabolism; D011878:Radiotherapy / Q000379:methods*; D022603:Shiga Toxins / Q000276:immunology; D014611:Vaccination / Q000379:methods*; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000199:Actins; D000941:Antigens; D019496:Cancer Vaccines; D018799:Intercellular Adhesion Molecule-1; D053918:Papillomavirus Vaccines; D011509:Proteoglycans; D022603:Shiga Toxins; D000099216:Chondroitin Sulfate Proteoglycan 4; C077239:stxB toxin