Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients

Niels Halama; Inka Zoernig; Anna Berthel; Christoph Kahlert; Fee Klupp; Meggy Suarez-Carmona; Thomas Suetterlin; Karsten Brand; Juergen Krauss; Felix Lasitschka; Tina Lerchl; Claudia Luckner-Minden; Alexis Ulrich; Moritz Koch; Juergen Weitz; Martin Schneider; Markus W Buechler; Laurence Zitvogel; Thomas Herrmann; Axel Benner; Christina Kunz; Stephan Luecke; Christoph Springfeld; Niels Grabe; Christine S Falk; Dirk Jaeger

doi:10.1016/j.ccell.2016.03.005

Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients

Cancer Cell. 2016 Apr 11;29(4):587-601. doi: 10.1016/j.ccell.2016.03.005.

Authors

Niels Halama¹, Inka Zoernig², Anna Berthel³, Christoph Kahlert⁴, Fee Klupp⁵, Meggy Suarez-Carmona², Thomas Suetterlin³, Karsten Brand⁶, Juergen Krauss², Felix Lasitschka⁶, Tina Lerchl³, Claudia Luckner-Minden², Alexis Ulrich⁵, Moritz Koch⁷, Juergen Weitz⁷, Martin Schneider⁵, Markus W Buechler⁵, Laurence Zitvogel⁸, Thomas Herrmann⁹, Axel Benner¹⁰, Christina Kunz¹⁰, Stephan Luecke¹⁰, Christoph Springfeld², Niels Grabe³, Christine S Falk¹¹, Dirk Jaeger³

Affiliations

¹ 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: [email protected].
² Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany.
³ 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.
⁴ Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany; Department of Surgery, University Hospital Dresden, 01307 Dresden, Germany.
⁵ Department of Surgery, University Hospital Heidelberg, 69120 Heidelberg, Germany.
⁶ Institute for Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany.
⁷ Department of Surgery, University Hospital Dresden, 01307 Dresden, Germany.
⁸ INSERM U1015, Institut Gustave Roussy (IGR), 94805 Villejuif, France.
⁹ Department of Internal Medicine I, Klinikum Idar-Oberstein, 55743 Idar Oberstein, Germany.
¹⁰ Division of Biostatistics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
¹¹ Institute of Transplant Immunology, Integrated Research and Treatment Center Transplantation, Hannover Medical School, 30625 Hannover, Germany.

PMID: 27070705
DOI: 10.1016/j.ccell.2016.03.005

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / drug therapy
Adenocarcinoma / immunology
Adenocarcinoma / secondary*
Apoptosis / drug effects
Chemokine CCL5 / antagonists & inhibitors*
Chemokine CCL5 / biosynthesis
Chemokine CCL5 / metabolism
Chemokines / physiology
Chemotaxis
Clinical Trials, Phase I as Topic
Clodronic Acid / pharmacology
Colorectal Neoplasms / immunology*
Cyclohexanes / pharmacology
Cyclohexanes / therapeutic use
Humans
Interferon-alpha / metabolism
Liver Neoplasms / drug therapy
Liver Neoplasms / immunology
Liver Neoplasms / metabolism
Liver Neoplasms / secondary*
Lung Neoplasms / drug therapy
Lung Neoplasms / secondary
Lymphocytes, Tumor-Infiltrating / immunology
Lymphocytes, Tumor-Infiltrating / metabolism
Macrophages / drug effects
Macrophages / metabolism
Maraviroc
Molecular Targeted Therapy*
NG-Nitroarginine Methyl Ester / pharmacology
Neoplasm Invasiveness
Neoplasm Proteins / antagonists & inhibitors*
Neoplasm Proteins / physiology
Phenylurea Compounds / therapeutic use
Pilot Projects
Pyridines / therapeutic use
Receptors, CCR5 / drug effects*
Receptors, CCR5 / metabolism
STAT3 Transcription Factor / physiology
Survival Analysis
Triazoles / pharmacology
Triazoles / therapeutic use
Tumor Cells, Cultured
Tumor Microenvironment / drug effects

Substances

CCL5 protein, human
CCR5 protein, human
Chemokine CCL5
Chemokines
Cyclohexanes
Interferon-alpha
Neoplasm Proteins
Phenylurea Compounds
Pyridines
Receptors, CCR5
STAT3 Transcription Factor
STAT3 protein, human
Triazoles
Clodronic Acid
regorafenib
Maraviroc
NG-Nitroarginine Methyl Ester