title: Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients.
abstract: The immune response influences the clinical course of colorectal cancer (CRC). Analyzing the invasive margin of human CRC liver metastases, we identified a mechanism of immune cell exploitation by tumor cells. While two distinct subsets of myeloid cells induce an influx of T cells into the invasive margin via CXCL9/CXCL10, CCL5 is produced by these T cells and stimulates pro-tumoral effects via CCR5. CCR5 blockade in patient-derived functional in vitro organotypic culture models showed a macrophage repolarization with anti-tumoral effects. These anti-tumoral effects were then confirmed in a phase I trial with a CCR5 antagonist in patients with liver metastases of advanced refractory CRC. Mitigation of tumor-promoting inflammation within the tumor tissue and objective tumor responses in CRC were observed.
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany; Institute for Immunology, University Hospital Heidelberg, 69120 Heidelberg, Germany. Electronic address: niels.halama@nct-heidelberg.de.
authors.forename: Niels
authors.initials: N
authors.lastname: Halama
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Inka
authors.initials: I
authors.lastname: Zoernig
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Berthel
authors.affiliation: Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany; Department of Surgery, University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Kahlert
authors.affiliation: Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Fee
authors.initials: F
authors.lastname: Klupp
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Meggy
authors.initials: M
authors.lastname: Suarez-Carmona
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Suetterlin
authors.affiliation: Institute for Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Karsten
authors.initials: K
authors.lastname: Brand
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Krauss
authors.affiliation: Institute for Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Lasitschka
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Tina
authors.initials: T
authors.lastname: Lerchl
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Luckner-Minden
authors.affiliation: Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Alexis
authors.initials: A
authors.lastname: Ulrich
authors.affiliation: Department of Surgery, University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Koch
authors.affiliation: Department of Surgery, University Hospital Dresden, 01307 Dresden, Germany.
authors.forename: Juergen
authors.initials: J
authors.lastname: Weitz
authors.affiliation: Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Markus W
authors.initials: MW
authors.lastname: Buechler
authors.affiliation: INSERM U1015, Institut Gustave Roussy (IGR), 94805 Villejuif, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Zitvogel
authors.affiliation: Department of Internal Medicine I, Klinikum Idar-Oberstein, 55743 Idar Oberstein, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Herrmann
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Kunz
authors.affiliation: Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Luecke
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Springfeld
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Niels
authors.initials: N
authors.lastname: Grabe
authors.affiliation: Institute of Transplant Immunology, Integrated Research and Treatment Center Transplantation, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Christine S
authors.initials: CS
authors.lastname: Falk
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tissue Imaging and Analysis Center, National Center for Tumor Diseases, BIOQUANT, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Jaeger
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000276:immunology / Q000556:secondary*; D017209:Apoptosis / Q000187:drug effects; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D018925:Chemokines / Q000502:physiology; D002633:Chemotaxis; D017321:Clinical Trials, Phase I as Topic; D004002:Clodronic Acid / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000276:immunology*; D003510:Cyclohexanes / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism / Q000556:secondary*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D000077592:Maraviroc; D058990:Molecular Targeted Therapy; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology; D010671:Phenylurea Compounds / Q000627:therapeutic use; D010865:Pilot Projects; D011725:Pyridines / Q000627:therapeutic use; D019713:Receptors, CCR5 / Q000187:drug effects* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000502:physiology; D016019:Survival Analysis; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: C483024:CCL5 protein, human; C584933:CCR5 protein, human; D018946:Chemokine CCL5; D018925:Chemokines; D003510:Cyclohexanes; D016898:Interferon-alpha; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D011725:Pyridines; D019713:Receptors, CCR5; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014230:Triazoles; D004002:Clodronic Acid; C559147:regorafenib; D000077592:Maraviroc; D019331:NG-Nitroarginine Methyl Ester