title: Radiotherapy combined with TLR7/8 activation induces strong immune responses against gastrointestinal tumors.
abstract: In addition to local cytotoxic activity, radiotherapy may also elicit local and systemic antitumor immunity, which may be augmented by immunotherapeutic agents including Toll-like receptor (TLR) 7/8 agonists. Here, we investigated the ability of 3M-011 (854A), a TLR7/8 agonist, to boost the antigen-presenting activity of dendritic cells (DC) as an adjuvant to radiotherapy. The combined treatment induced marked local and systemic responses in subcutaneous and orthotopic mouse models of colorectal and pancreatic cancer. In vitro cytotoxicity assays as well as in vivo depletion experiments with monoclonal antibodies identified NK and CD8 T cells as the cell populations mediating the cytotoxic effects of the treatment, while in vivo depletion of CD11c+ dendritic cells (DC) in CD11c-DTR transgenic mice revealed DC as the pivotal immune hub in this setting. The specificity of the immune reaction was confirmed by ELISPOT assays. TLR7/8 agonists therefore seem to be potent adjuvants to radiotherapy, inducing strong local and profound systemic immune responses to tumor antigens released by conventional therapy.
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.|CCU Molecular and Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany.|Department of Radiation Oncology, University Hospital Center, 69120 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schölch
authors.affiliation: Department of General, Gastrointestinal and Transplant Surgery, University Hospital Heidelberg, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany.|CCU Molecular and Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany.|Department of Radiation Oncology, University Hospital Center, 69120 Heidelberg, Germany.
authors.forename: Conrad
authors.initials: C
authors.lastname: Rauber
authors.affiliation: CCU Molecular and Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany.|Department of Radiation Oncology, University Hospital Center, 69120 Heidelberg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Tietz
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Nuh N
authors.initials: NN
authors.lastname: Rahbari
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Bork
authors.affiliation: Department of General, Gastrointestinal and Transplant Surgery, University Hospital Heidelberg, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kahlert
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, University Hospital Heidelberg, Ruprecht-Karls-Universität Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Haberkorn
authors.affiliation: 3M, Inc., St. Paul, Minnesota 55121, USA.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tomai
authors.affiliation: Fibrogen Inc., San Francisco, California 94158, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lipson
authors.affiliation: Division of Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany.
authors.forename: Rafael
authors.initials: R
authors.lastname: Carretero
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Koch
authors.affiliation: CCU Molecular and Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany.|Department of Radiation Oncology, University Hospital Center, 69120 Heidelberg, Germany.
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D003131:Combined Modality Therapy; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007124:Immunoenzyme Techniques; D007167:Immunotherapy; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D011804:Quinolines / Q000494:pharmacology; D011839:Radiation, Ionizing; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists*; D051200:Toll-Like Receptor 8 / Q000819:agonists*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: C526116:3M 001; D016207:Cytokines; D007093:Imidazoles; D011804:Quinolines; C495348:TLR7 protein, human; C495349:TLR8 protein, human; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8
keywords: TLR7/8 ligand; colorectal cancer; immunotherapy; pancreatic cancer; radiotherapy