title: Cancer-targeted IL-12 controls human rhabdomyosarcoma by senescence induction and myogenic differentiation.
abstract: Stimulating the immune system to attack cancer is a promising approach, even for the control of advanced cancers. Several cytokines that promote interferon-γ-dominated immune responses show antitumor activity, with interleukin 12 (IL-12) being of major importance. Here, we used an antibody-IL-12 fusion protein (NHS-IL12) that binds histones of necrotic cells to treat human sarcoma in humanized mice. Following sarcoma engraftment, NHS-IL12 therapy was combined with either engineered IL-7 (FcIL-7) or IL-2 (IL-2MAB602) for continuous cytokine bioavailability. NHS-IL12 strongly induced innate and adaptive antitumor immunity when combined with IL-7 or IL-2. NHS-IL12 therapy significantly improved survival of sarcoma-bearing mice and caused long-term remissions when combined with IL-2. NHS-IL12 induced pronounced cancer cell senescence, as documented by strong expression of senescence-associated p16INK4aand nuclear translocation of p-HP1γ, and permanent arrest of cancer cell proliferation. In addition, this cancer immunotherapy initiated the induction of myogenic differentiation, further promoting the hypothesis that efficient antitumor immunity includes mechanisms different from cytotoxicity for efficient cancer controlin vivo.
authors.affiliation: Department of General Pediatrics; Oncology/Hematology; University Children's Hospital ; Tübingen, Germany.
authors.forename: Karin
authors.initials: K
authors.lastname: Schilbach
authors.affiliation: Department of General Pediatrics; Oncology/Hematology; University Children's Hospital ; Tübingen, Germany.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Alkhaled
authors.affiliation: Department of General Pediatrics; Oncology/Hematology; University Children's Hospital ; Tübingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Welker
authors.affiliation: Department of Radiation Oncology; Eberhard Karls University ; Tübingen, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Eckert
authors.affiliation: Department of General, Visceral and Transplant Surgery; University Hospital ; Tübingen, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Blank
authors.affiliation: Department of General Pediatrics; Oncology/Hematology; University Children's Hospital ; Tübingen, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Ziegler
authors.affiliation: Department of General Pediatrics; Oncology/Hematology; University Children's Hospital ; Tübingen, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Sterk
authors.affiliation: Department of General Pediatrics; Oncology/Hematology; University Children's Hospital ; Tübingen, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Müller
authors.affiliation: Department of General Pediatrics; Oncology/Hematology; University Children's Hospital ; Tübingen, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Sonntag
authors.affiliation: Department of Dermatology; Eberhard Karls University ; Tübingen, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wieder
authors.affiliation: Department of Dermatology; Eberhard Karls University ; Tübingen, Germany.
authors.forename: Heidi
authors.initials: H
authors.lastname: Braumüller
authors.affiliation: Werner Siemens Imaging Center; Department for Preclinical Imaging and Radiopharmacy; Eberhard Karls University ; Tübingen, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Schmitt
authors.affiliation: University of Würzburg; Department of Pediatrics; Interdisciplinary Stem Cell Laboratory ; Würzburg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Eyrich
authors.affiliation: Department of General Pediatrics; Oncology/Hematology; University Children's Hospital ; Tübingen, Germany.
authors.forename: Sabine
authors.initials: S
authors.lastname: Schleicher
authors.affiliation: Department of General Pediatrics; Oncology/Hematology; University Children's Hospital ; Tübingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Seitz
authors.affiliation: Department of General Pediatrics; Oncology/Hematology; University Children's Hospital ; Tübingen, Germany.
authors.forename: Annika
authors.initials: A
authors.lastname: Erbacher
authors.affiliation: Werner Siemens Imaging Center; Department for Preclinical Imaging and Radiopharmacy; Eberhard Karls University ; Tübingen, Germany.
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Pichler
authors.affiliation: Department of General Pathology; Institute of Pathology; Eberhard Karls University ; Tübingen, Germany.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Müller
authors.affiliation: EMD Serono Research Institute ; Billerica, MA USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Tighe
authors.affiliation: Départment d'Immunologie; Institute Pasteur ; Paris, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Lim
authors.affiliation: Provenance Biopharmaceuticals ; Carlisle, MA USA.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Gillies
authors.affiliation: Merck Serono R&D; Global Early Development; Merck KGaA ; Darmstadt, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Strittmatter
authors.affiliation: Department of Dermatology; Eberhard Karls University ; Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Röcken
authors.affiliation: Department of General Pediatrics; Oncology/Hematology; University Children's Hospital ; Tübingen, Germany.
authors.forename: Rupert
authors.initials: R
authors.lastname: Handgretinger
keywords: CIP1, CDK-interacting protein 1; DNAM-1, DNAX accessory molecule-1; KIR, killer-cell immunoglobulin-like receptor; M1/M2 macrophages; MICA/B, MHC class I polypeptide-related sequence A/B; NKG, natural killer group; NSG, NOD SCID gamma chain knock out mouse; PCNA, proliferating cell nuclear antigen; PVR, poliovirus receptor; RMS, rhabdomyosarcoma, (eRMS: embryonal, aRMS: alveolar); ROI, region of interest; RORC, RAR-related orphan receptor C; SCT, stem cell transplantation; SPECT/CT, single-photon emission computed tomography; TH1-induced senescence; TH17 cells; TRBV, T-cell receptor beta chain; ULBP, UL16 binding protein; WAF, wild-type activating fragment; cancer-targeted IL-12; differentiation; humanized mice; immunocytokine; immunotherapy; pHP1γ, phosphorylated heterochromatin protein 1 gamma; rhabdomyosarcoma; tumor-infiltrating lymphocytes