title: Combinatorial immunotherapy of polyinosinic-polycytidylic acid and blockade of programmed death-ligand 1 induce effective CD8 T-cell responses against established tumors.
abstract: OBJECTIVE
  Epitope-based cancer vaccines capable of inducing CD8 T-cell responses to tumor-associated antigens (TAA) expressed by tumor cells have been considered as attractive alternatives for the treatment of some types of cancer. However, reliable TAAs have not been identified for most malignant diseases, limiting the development of epitope-based vaccines. Herein, we report that the combinatorial therapy of polyinosinic-polycytidylic acid (poly-IC) and antiprogrammed death-ligand 1 (PD-L1) monoclonal antibody (mAb) can be implemented with good results for tumors where no known TAAs have been identified.
  
  
  METHODS
  Three cancer mouse models (melanoma, lung, and colon) were used to evaluate therapeutic efficacy and examine the immunologic mechanisms of the poly-IC/anti-PD-L1 mAb therapy.
  
  
  RESULTS
  The combined administration of poly-IC and anti-PD-L1 mAb into tumor-bearing mice generated potent immune responses resulting in the complete eradication or remarkable reduction of tumor growth. In some instances, the poly-IC/anti-PD-L1 mAb therapy induced long-lasting protection against tumor rechallenges. The results indicate that CD8 T cells but not CD4 T cells or NK cells mediated the therapeutic efficacy of this combinatorial therapy. Experiments using genetically deficient mice indicate that the therapeutic efficacy of this combinatorial therapy depended in part by the participation of type-I IFN, whereas IFN-γ did not seem to play a major role.
  
  
  CONCLUSIONS
  The overall results suggest that immunotherapy consisting of the combination of poly-IC/anti-PD-L1 mAb could be a promising new approach for treating patients with cancer, especially those instances where no reliable TAAs are available as a therapeutic vaccine.
authors.affiliation: Authors' Affiliations: Immunology Program, Moffitt Cancer Center; Departments of Oncologic Sciences and Molecular Medicine, University of South Florida, Tampa, Florida; and Department of Otolaryngology-Head and Neck Surgery, Asahikawa Medical University, Asahikawa, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nagato
authors.forename: Young-Ran
authors.initials: YR
authors.lastname: Lee
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Harabuchi
authors.forename: Esteban
authors.initials: E
authors.lastname: Celis
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007370:Interferon Type I / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008546:Melanoma, Experimental; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D011070:Poly I-C / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D060890:B7-H1 Antigen; D007370:Interferon Type I; D007371:Interferon-gamma; D011070:Poly I-C