Reactive neutrophil responses dependent on the receptor tyrosine kinase c-MET limit cancer immunotherapy
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 infiltrati...
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| Main Authors: | , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
October 17, 2017
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| In: |
Immunity
Year: 2017, Volume: 47, Issue: 4, Pages: 789-802.e9 |
| ISSN: | 1097-4180 |
| DOI: | 10.1016/j.immuni.2017.09.012 |
| Online Access: | Verlag, Volltext: http://dx.doi.org/10.1016/j.immuni.2017.09.012 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S1074761317304235 
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| Author Notes: | Nicole Glodde, Tobias Bald, Debby van den Boorn-Konijnenberg, Kyohei Nakamura, Jake S. O’Donnell, Sabrina Szczepanski, Maria Brandes, Sarah Eickhoff, Indrajit Das, Naveen Shridhar, Daniel Hinze, Meri Rogava, Tetje C. van der Sluis, Janne J. Ruotsalainen, Evelyn Gaffal, Jennifer Landsberg, Kerstin U. Ludwig, Christoph Wilhelm, Monika Riek-Burchardt, Andreas J. Müller, Christoffer Gebhardt, Richard A. Scolyer, Georgina V. Long, Viktor Janzen, Michele W.L. Teng, Wolfgang Kastenmüller, Massimiliano Mazzone, Mark J. Smyth, Thomas Tüting, and Michael Hölzel |
| Summary: | 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. |
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| Item Description: | Gesehen am 08.11.2018 |
| Physical Description: | Online Resource |
| ISSN: | 1097-4180 |
| DOI: | 10.1016/j.immuni.2017.09.012 |