title: Blocking Indolamine-2,3-Dioxygenase Rebound Immune Suppression Boosts Antitumor Effects of Radio-Immunotherapy in Murine Models and Spontaneous Canine Malignancies.
abstract: OBJECTIVE
  Previous studies demonstrate that intratumoral CpG immunotherapy in combination with radiotherapy acts as an in-situ vaccine inducing antitumor immune responses capable of eradicating systemic disease. Unfortunately, most patients fail to respond. We hypothesized that immunotherapy can paradoxically upregulate immunosuppressive pathways, a phenomenon we term "rebound immune suppression," limiting clinical responses. We further hypothesized that the immunosuppressive enzyme indolamine-2,3-dioxygenase (IDO) is a mechanism of rebound immune suppression and that IDO blockade would improve immunotherapy efficacy.
  
  
  METHODS
  We examined the efficacy and immunologic effects of a novel triple therapy consisting of local radiotherapy, intratumoral CpG, and systemic IDO blockade in murine models and a pilot canine clinical trial.
  
  
  RESULTS
  In murine models, we observed marked increase in intratumoral IDO expression after treatment with radiotherapy, CpG, or other immunotherapies. The addition of IDO blockade to radiotherapy + CpG decreased IDO activity, reduced tumor growth, and reduced immunosuppressive factors, such as regulatory T cells in the tumor microenvironment. This triple combination induced systemic antitumor effects, decreasing metastases, and improving survival in a CD8(+) T-cell-dependent manner. We evaluated this novel triple therapy in a canine clinical trial, because spontaneous canine malignancies closely reflect human cancer. Mirroring our mouse studies, the therapy was well tolerated, reduced intratumoral immunosuppression, and induced robust systemic antitumor effects.
  
  
  CONCLUSIONS
  These results suggest that IDO maintains immune suppression in the tumor after therapy, and IDO blockade promotes a local antitumor immune response with systemic consequences. The efficacy and limited toxicity of this strategy are attractive for clinical translation. Clin Cancer Res; 22(17); 4328-40. ©2016 AACR.
authors.affiliation: Department of Radiation Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California. ammonjazeb@ucdavis.edu.
authors.forename: Arta M
authors.initials: AM
authors.lastname: Monjazeb
authors.affiliation: Department of Surgical and Radiological Sciences, UC Davis School of Veterinary Medicine, Davis, California.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Kent
authors.affiliation: Department of Dermatology, UC Davis Health Sciences, Sacramento, California.
authors.forename: Steven K
authors.initials: SK
authors.lastname: Grossenbacher
authors.affiliation: Department of Dermatology, UC Davis Health Sciences, Sacramento, California.
authors.forename: Christine
authors.initials: C
authors.lastname: Mall
authors.affiliation: Department of Dermatology, UC Davis Health Sciences, Sacramento, California.
authors.forename: Anthony E
authors.initials: AE
authors.lastname: Zamora
authors.affiliation: Department of Dermatology, UC Davis Health Sciences, Sacramento, California.
authors.forename: Annie
authors.initials: A
authors.lastname: Mirsoian
authors.affiliation: Department of Pathology, UC Davis Health Sciences, Sacramento, California.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Chen
authors.affiliation: Department of Pathology, Microbiology, and Immunology, UC Davis School of Veterinary Medicine, Davis, California.
authors.forename: Amir
authors.initials: A
authors.lastname: Kol
authors.affiliation: Departments of Radiation Oncology and Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Shiao
authors.affiliation: Department of Radiation Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California.
authors.forename: Abhinav
authors.initials: A
authors.lastname: Reddy
authors.affiliation: Department of Radiation Oncology, UC Davis Comprehensive Cancer Center, Sacramento, California.
authors.forename: Julian R
authors.initials: JR
authors.lastname: Perks
authors.affiliation: Department of Surgical and Radiological Sciences, UC Davis School of Veterinary Medicine, Davis, California.
authors.forename: William
authors.initials: W
authors.lastname: T N Culp
authors.affiliation: Department of Surgical and Radiological Sciences, UC Davis School of Veterinary Medicine, Davis, California.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Sparger
authors.affiliation: Division of Surgical Oncology, Department of Surgery, UC Davis Comprehensive Cancer Center, Sacramento, California.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Canter
authors.affiliation: Department of Dermatology, UC Davis Health Sciences, Sacramento, California.
authors.forename: Gail D
authors.initials: GD
authors.lastname: Sckisel
authors.affiliation: Department of Dermatology, UC Davis Health Sciences, Sacramento, California. Division of Hematology and Oncology, Department of Internal Medicine, UC Davis Comprehensive Cancer Center, Sacramento, California.
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004285:Dogs; D004789:Enzyme Activation; D005260:Female; D056747:Immunomodulation / Q000187:drug effects*; D007165:Immunosuppression Therapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors*; D008546:Melanoma, Experimental; D051379:Mice; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality / Q000628:therapy; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage; D016499:Radioimmunotherapy / Q000379:methods; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D009838:Oligodeoxyribonucleotides