title: Low-dose irradiation programs macrophage differentiation to an iNOS⁺/M1 phenotype that orchestrates effective T cell immunotherapy.
abstract: Inefficient T cell migration is a major limitation of cancer immunotherapy. Targeted activation of the tumor microenvironment may overcome this barrier. We demonstrate that neoadjuvant local low-dose gamma irradiation (LDI) causes normalization of aberrant vasculature and efficient recruitment of tumor-specific T cells in human pancreatic carcinomas and T-cell-mediated tumor rejection and prolonged survival in otherwise immune refractory spontaneous and xenotransplant mouse tumor models. LDI (local or pre-adoptive-transfer) programs the differentiation of iNOS⁺ M1 macrophages that orchestrate CTL recruitment into and killing within solid tumors through iNOS by inducing endothelial activation and the expression of TH1 chemokines and by suppressing the production of angiogenic, immunosuppressive, and tumor growth factors.
authors.affiliation: Division of Translational Immunology, German Cancer Research Center (DKFZ) and National Center of Tumor Diseases (NCT), 69120 Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Klug
authors.forename: Hridayesh
authors.initials: H
authors.lastname: Prakash
authors.forename: Peter E
authors.initials: PE
authors.lastname: Huber
authors.forename: Tobias
authors.initials: T
authors.lastname: Seibel
authors.forename: Noemi
authors.initials: N
authors.lastname: Bender
authors.forename: Niels
authors.initials: N
authors.lastname: Halama
authors.forename: Christina
authors.initials: C
authors.lastname: Pfirschke
authors.forename: Ralf Holger
authors.initials: RH
authors.lastname: Voss
authors.forename: Carmen
authors.initials: C
authors.lastname: Timke
authors.forename: Ludmila
authors.initials: L
authors.lastname: Umansky
authors.forename: Kay
authors.initials: K
authors.lastname: Klapproth
authors.forename: Knut
authors.initials: K
authors.lastname: Schäkel
authors.forename: Natalio
authors.initials: N
authors.lastname: Garbi
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.forename: Jürgen
authors.initials: J
authors.lastname: Weitz
authors.forename: Hubertus
authors.initials: H
authors.lastname: Schmitz-Winnenthal
authors.forename: Günter J
authors.initials: GJ
authors.lastname: Hämmerling
authors.forename: Philipp
authors.initials: P
authors.lastname: Beckhove
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002454:Cell Differentiation / Q000528:radiation effects; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive; D018836:Inflammation Mediators / Q000378:metabolism; D007340:Insulinoma / Q000098:blood supply / Q000276:immunology / Q000628:therapy*; D008264:Macrophages / Q000502:physiology* / Q000528:radiation effects; D008545:Melanoma / Q000276:immunology / Q000628:therapy; D051379:Mice; D008809:Mice, Inbred C3H; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000276:immunology / Q000628:therapy*; D010641:Phenotype; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D011879:Radiotherapy Dosage; D018714:Radiotherapy, Adjuvant; D019139:Tumor Escape; D014611:Vaccination
chemical_list: D018836:Inflammation Mediators; D019408:Platelet Endothelial Cell Adhesion Molecule-1; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II