Format

Send to

Choose Destination
Immunity. 2017 Oct 17;47(4):789-802.e9. doi: 10.1016/j.immuni.2017.09.012.

Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy.

Author information

1
Laboratory of Experimental Dermatology, Department of Dermatology, University of Magdeburg, 39120 Magdeburg, Germany; Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53105 Bonn, Germany; Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany.
2
Laboratory of Experimental Dermatology, Department of Dermatology, University of Magdeburg, 39120 Magdeburg, Germany; Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53105 Bonn, Germany; Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia. Electronic address: tobias.bald@qimrberghofer.edu.au.
3
Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany.
4
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia.
5
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Medicine, The University of Queensland, Herston, QLD 4006, Australia.
6
Department of Internal Medicine III, Hematology/Oncology/Rheumatology, University of Bonn, 53105 Bonn, Germany.
7
Laboratory for Cellular Interactions and Immunimaging, Institute of Experimental Immunology, University of Bonn, 53105 Bonn, Germany.
8
Laboratory of Experimental Dermatology, Department of Dermatology, University of Magdeburg, 39120 Magdeburg, Germany; Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53105 Bonn, Germany.
9
Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53105 Bonn, Germany.
10
Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, 53127 Bonn, Germany.
11
Unit for Immunopathology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany.
12
Institute of Molecular and Clinical Immunology, University of Magdeburg, 39120 Magdeburg, Germany.
13
Institute of Molecular and Clinical Immunology, University of Magdeburg, 39120 Magdeburg, Germany; Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany.
14
Skin Cancer Unit, German Cancer Research Center, Heidelberg and Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht Karl University of Heidelberg, 69121 Heidelberg, Germany.
15
Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia; Melanoma Institute Australia and Sydney Medical School, The University of Sydney, Sydney, NSW 2065, Australia.
16
Melanoma Institute Australia and Sydney Medical School, The University of Sydney, Sydney, NSW 2065, Australia.
17
Cancer Immunoregulation and Immunotherapy Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Medicine, The University of Queensland, Herston, QLD 4006, Australia.
18
Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven B3000, Belgium; Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven B3000, Belgium.
19
Immunology in Cancer and Infection Laboratory, QIMR Berghofer Medical Research Institute, Herston, QLD 4006, Australia; School of Medicine, The University of Queensland, Herston, QLD 4006, Australia.
20
Laboratory of Experimental Dermatology, Department of Dermatology, University of Magdeburg, 39120 Magdeburg, Germany; Laboratory of Experimental Dermatology, Department of Dermatology and Allergy, University of Bonn, 53105 Bonn, Germany. Electronic address: thomas.tueting@med.ovgu.de.
21
Unit for RNA Biology, Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, 53105 Bonn, Germany. Electronic address: michael.hoelzel@ukbonn.de.

Abstract

Inhibitors of the receptor tyrosine kinase c-MET are currently used in the clinic to target oncogenic signaling in tumor cells. We found that concomitant c-MET inhibition promoted adoptive T cell transfer and checkpoint immunotherapies in murine cancer models by increasing effector T cell infiltration in tumors. This therapeutic effect was independent of tumor cell-intrinsic c-MET dependence. Mechanistically, c-MET inhibition impaired the reactive mobilization and recruitment of neutrophils into tumors and draining lymph nodes in response to cytotoxic immunotherapies. In the absence of c-MET inhibition, neutrophils recruited to T cell-inflamed microenvironments rapidly acquired immunosuppressive properties, restraining T cell expansion and effector functions. In cancer patients, high serum levels of the c-MET ligand HGF correlated with increasing neutrophil counts and poor responses to checkpoint blockade therapies. Our findings reveal a role for the HGF/c-MET pathway in neutrophil recruitment and function and suggest that c-MET inhibitor co-treatment may improve responses to cancer immunotherapy in settings beyond c-MET-dependent tumors.

KEYWORDS:

HGF; T cells; bone marrow; c-MET; cancer immunotherapy; lymph node; melanoma; neutrophils; plasticity; therapy resistance

PMID:
29045907
DOI:
10.1016/j.immuni.2017.09.012
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center