title: Immune cell-poor melanomas benefit from PD-1 blockade after targeted type I IFN activation.
abstract: Infiltration of human melanomas with cytotoxic immune cells correlates with spontaneous type I IFN activation and a favorable prognosis. Therapeutic blockade of immune-inhibitory receptors in patients with preexisting lymphocytic infiltrates prolongs survival, but new complementary strategies are needed to activate cellular antitumor immunity in immune cell-poor melanomas. Here, we show that primary melanomas in Hgf-Cdk4(R24C) mice, which imitate human immune cell-poor melanomas with a poor outcome, escape IFN-induced immune surveillance and editing. Peritumoral injections of immunostimulatory RNA initiated a cytotoxic inflammatory response in the tumor microenvironment and significantly impaired tumor growth. This critically required the coordinated induction of type I IFN responses by dendritic, myeloid, natural killer, and T cells. Importantly, antibody-mediated blockade of the IFN-induced immune-inhibitory interaction between PD-L1 and PD-1 receptors further prolonged the survival. These results highlight important interconnections between type I IFNs and immune-inhibitory receptors in melanoma pathogenesis, which serve as targets for combination immunotherapies.
  
  
  CONCLUSIONS
  Using a genetically engineered mouse melanoma model, we demonstrate that targeted activation of the type I IFN system with immunostimulatory RNA in combination with blockade of immune-inhibitory receptors is a rational strategy to expose immune cell-poor tumors to cellular immune surveillance.
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bald
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Landsberg
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Dorys
authors.initials: D
authors.lastname: Lopez-Ramos
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Marcel
authors.initials: M
authors.lastname: Renn
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Nicole
authors.initials: N
authors.lastname: Glodde
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Philipp
authors.initials: P
authors.lastname: Jansen
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Evelyn
authors.initials: E
authors.lastname: Gaffal
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Julia
authors.initials: J
authors.lastname: Steitz
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Rene
authors.initials: R
authors.lastname: Tolba
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Limmer
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Michael
authors.initials: M
authors.lastname: Hölzel
authors.affiliation: Authors' Affiliations:Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, Department of Orthopaedics and Trauma Surgery, Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn; Institute for Laboratory Animal Science, University Hospital, RWTH Aachen University, Aachen; Twincore, Centre for Experimental and Clinical Infection Research, Hannover, Germany; and Department of Oncology, Clinical Sciences, Lund University, Lund, Sweden thomas.tueting@ukb.uni-bonn.de.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tüting
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D060890:B7-H1 Antigen / Q000276:immunology; D002273:Carcinogens; D007074:Immunoglobulin G / Q000008:administration & dosage; D007155:Immunologic Factors / Q000008:administration & dosage; D007370:Interferon Type I / Q000276:immunology*; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000276:immunology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011070:Poly I-C / Q000008:administration & dosage; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000276:immunology; D012313:RNA / Q000008:administration & dosage; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D060890:B7-H1 Antigen; D002273:Carcinogens; C498919:Cd274 protein, mouse; D007074:Immunoglobulin G; D007155:Immunologic Factors; D007370:Interferon Type I; D061026:Programmed Cell Death 1 Receptor; D015127:9,10-Dimethyl-1,2-benzanthracene; D012313:RNA; D011070:Poly I-C