Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy
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Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy. / Glodde, Nicole; Bald, Tobias; van den Boorn-Konijnenberg, Debby; Nakamura, Kyohei; O'Donnell, Jake S; Szczepanski, Sabrina; Brandes, Maria; Eickhoff, Sarah; Das, Indrajit; Shridhar, Naveen; Hinze, Daniel; Rogava, Meri; van der Sluis, Tetje C; Ruotsalainen, Janne J; Gaffal, Evelyn; Landsberg, Jennifer; Ludwig, Kerstin U; Wilhelm, Christoph; Riek-Burchardt, Monika; Müller, Andreas J; Gebhardt, Christoffer; Scolyer, Richard A; Long, Georgina V; Janzen, Viktor; Teng, Michele W L; Kastenmüller, Wolfgang; Mazzone, Massimiliano; Smyth, Mark J; Tüting, Thomas; Hölzel, Michael.
in: IMMUNITY, Jahrgang 47, Nr. 4, 17.10.2017, S. 789-802.e9.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy
AU - Glodde, Nicole
AU - Bald, Tobias
AU - van den Boorn-Konijnenberg, Debby
AU - Nakamura, Kyohei
AU - O'Donnell, Jake S
AU - Szczepanski, Sabrina
AU - Brandes, Maria
AU - Eickhoff, Sarah
AU - Das, Indrajit
AU - Shridhar, Naveen
AU - Hinze, Daniel
AU - Rogava, Meri
AU - van der Sluis, Tetje C
AU - Ruotsalainen, Janne J
AU - Gaffal, Evelyn
AU - Landsberg, Jennifer
AU - Ludwig, Kerstin U
AU - Wilhelm, Christoph
AU - Riek-Burchardt, Monika
AU - Müller, Andreas J
AU - Gebhardt, Christoffer
AU - Scolyer, Richard A
AU - Long, Georgina V
AU - Janzen, Viktor
AU - Teng, Michele W L
AU - Kastenmüller, Wolfgang
AU - Mazzone, Massimiliano
AU - Smyth, Mark J
AU - Tüting, Thomas
AU - Hölzel, Michael
N1 - Copyright © 2017 Elsevier Inc. All rights reserved.
PY - 2017/10/17
Y1 - 2017/10/17
N2 - 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.
AB - 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.
KW - Animals
KW - Cell Line, Tumor
KW - Cell Proliferation
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Neoplastic
KW - Immunotherapy
KW - Interferon-gamma
KW - Kaplan-Meier Estimate
KW - Mice, Inbred BALB C
KW - Mice, Inbred C57BL
KW - Mice, Knockout
KW - Mice, Transgenic
KW - Neoplasms, Experimental
KW - Neutrophils
KW - Proto-Oncogene Proteins c-met
KW - Signal Transduction
KW - T-Lymphocytes
KW - Tumor Microenvironment
KW - Journal Article
U2 - 10.1016/j.immuni.2017.09.012
DO - 10.1016/j.immuni.2017.09.012
M3 - SCORING: Journal article
C2 - 29045907
VL - 47
SP - 789-802.e9
JO - IMMUNITY
JF - IMMUNITY
SN - 1074-7613
IS - 4
ER -