Radiotherapy combined with TLR7/8 activation induces strong immune responses against gastrointestinal tumors

// Sebastian Scholch 1,3,4,* , Conrad Rauber 2,3,4,* , Alexandra Tietz 3,4 , Nuh N. Rahbari 1 , Ulrich Bork 1 , Thomas Schmidt 2 , Christoph Kahlert 1 , Uwe Haberkorn 5 , Mark A. Tomai 6 , Kenneth E. Lipson 7 , Rafael Carretero 8 , Jurgen Weitz 1 , Moritz Koch 1,** and Peter E. Huber 3,4,** 1 Department of Gastrointestinal, Thoracic and Vascular Surgery, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, 01307 Dresden, Germany 2 Department of General, Gastrointestinal and Transplant Surgery, University Hospital Heidelberg, Ruprecht-Karls-Universitat Heidelberg, 69120 Heidelberg, Germany 3 CCU Molecular and Radiation Oncology, German Cancer Research Center, 69120 Heidelberg, Germany 4 Department of Radiation Oncology, University Hospital Center, 69120 Heidelberg, Germany 5 Division of Nuclear Medicine, Department of Radiology, University Hospital Heidelberg, Ruprecht-Karls-Universitat Heidelberg, 69120 Heidelberg, Germany 6 3M, Inc., St. Paul, Minnesota 55121, USA 7 Fibrogen Inc., San Francisco, California 94158, USA 8 Division of Molecular Immunology, German Cancer Research Center, 69120 Heidelberg, Germany * These authors contributed equally to this work ** These authors share senior authorship Correspondence: Sebastian Scholch, email: // Keywords : colorectal cancer, pancreatic cancer, TLR7/8 ligand, radiotherapy, immunotherapy Received : November 29, 2014 Accepted : December 26, 2014 Published : December 31, 2014 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.