title: Antitumor Efficacy of Radiation plus Immunotherapy Depends upon Dendritic Cell Activation of Effector CD8+ T Cells.
abstract: Tumor cells dying after cytotoxic therapy are a potential source of antigen for T-cell priming. Antigen-presenting cells (APC) can cross-present MHC I-restricted peptides after the uptake of dying cells. Depending on the nature of the surrounding environmental signals, APCs then orchestrate a spectrum of responses ranging from immune activation to inhibition. Previously, we had demonstrated that combining radiation with either agonistic monoclonal antibody (mAb) to CD40 or a systemically administered TLR7 agonist could enhance CD8 T-cell-dependent protection against syngeneic murine lymphoma models. However, it remains unknown how individual APC populations affect this antitumor immune response. Using APC depletion models, we now show that dendritic cells (DC), but not macrophages or B cells, were responsible for the generation of long-term immunologic protection following combination therapy with radiotherapy and either agonistic CD40 mAb or systemic TLR7 agonist therapy. Novel immunotherapeutic approaches that augment antigen uptake and presentation by DCs may further enhance the generation of therapeutic antitumor immune responses, leading to improved outcomes after radiotherapy. Cancer Immunol Res; 4(7); 621-30. ©2016 AACR.
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Dovedi
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom.
authors.forename: Grazyna
authors.initials: G
authors.lastname: Lipowska-Bhalla
authors.affiliation: Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Beers
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom.
authors.forename: Eleanor J
authors.initials: EJ
authors.lastname: Cheadle
authors.affiliation: The Second Affiliated Hospital, Dalian Medical University, Dalian 116027, China.
authors.forename: Lijun
authors.initials: L
authors.lastname: Mu
authors.affiliation: Antibody and Vaccine Group, Cancer Sciences Unit, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Glennie
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom.|Christie NHS Trust, University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Illidge
authors.affiliation: Targeted Therapy Group, Institute of Cancer Sciences, University of Manchester, Manchester Academic Health Sciences Centre, United Kingdom.
authors.forename: Jamie
authors.initials: J
authors.lastname: Honeychurch
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D019013:CD40 Antigens / Q000037:antagonists & inhibitors / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000528:radiation effects; 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; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000276:immunology*; D008212:Lymphocyte Depletion; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D010587:Phagocytosis; D011878:Radiotherapy
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D016207:Cytokines