Targeting myeloid suppressive cells revives cytotoxic anti-tumor responses in pancreatic cancer
Dhifaf Sarhan,
Silke Eisinger,
Fei He,
Maria Bergsland,
Catarina Pelicano,
Caroline Driescher,
Kajsa Westberg,
Itziar Ibarlucea Benitez,
Rawan Humoud,
Giorgia Palano,
Shuijie Li,
Valentina Carannante,
Jonas Muhr,
Björn Önfelt,
Susanne Schlisio,
Jeffrey V. Ravetch,
Rainer Heuchel,
Matthias J. Löhr,
Mikael C.I. Karlsson
Affiliations
Dhifaf Sarhan
Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden, SE-141 521
Silke Eisinger
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Fei He
Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden, SE-141 521
Maria Bergsland
Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Catarina Pelicano
University of Cambridge, Cancer Research UK Cambridge Institute, Cambridge, UK
Caroline Driescher
Department of Pathology, Heinrich-Heine University of Düsseldorf, 40225 Düsseldorf, Germany
Kajsa Westberg
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Itziar Ibarlucea Benitez
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA
Rawan Humoud
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Giorgia Palano
Department of Medicine, Karolinska University Hospital, Huddinge, Sweden
Shuijie Li
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Valentina Carannante
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Jonas Muhr
Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Björn Önfelt
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Applied Physics, Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden
Susanne Schlisio
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
Jeffrey V. Ravetch
Laboratory of Molecular Genetics and Immunology, The Rockefeller University, New York, NY 10065, USA
Rainer Heuchel
Pancreatic Cancer Research Lab, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, SE-141 86 Stockholm, Sweden
Matthias J. Löhr
Pancreatic Cancer Research Lab, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, SE-141 86 Stockholm, Sweden
Mikael C.I. Karlsson
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Corresponding author
Summary: Immunotherapy for cancer that aims to promote T cell anti-tumor activity has changed current clinical practice, where some previously lethal cancers have now become treatable. However, clinical trials with low response rates have been disappointing for pancreatic ductal adenocarcinoma (PDAC). One suggested explanation is the accumulation of dominantly immunosuppressive tumor-associated macrophages and myeloid-derived suppressor cells in the tumor microenvironment (TME). Using retrospectively collected tumor specimens and transcriptomic data from PDAC, we demonstrate that expression of the scavenger receptor MARCO correlates with poor prognosis and a lymphocyte-excluding tumor phenotype. PDAC cell lines produce IL-10 and induce high expression of MARCO in myeloid cells, and this was further enhanced during hypoxic conditions. These myeloid cells suppressed effector T and natural killer (NK) cells and blocked NK cell tumor infiltration and tumor killing in a PDAC 3D-spheroid model. Anti-human MARCO (anti-hMARCO) antibody targeting triggered the repolarization of tumor-associated macrophages and activated the inflammasome machinery, resulting in IL-18 production. This in turn enhanced T cell and NK cell functions. The targeting of MARCO thus remodels the TME and represents a rational approach to make immunotherapy more efficient in PDAC patients.
