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.

Authors	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; Mueller, Andreas J.; Gebhardt, Christoffer; Scolyer, Richard A.; Long, Georgina V.; Janzen, Viktor; Teng, Michele W. L.; Kastenmueller, Wolfgang; Mazzone, Massimiliano; Smyth, Mark J.; Tueting, Thomas; Hoelzel, Michael
Journal	IMMUNITY
Pages	789-+
Volume	47
Date	1/10/2017
Grant ID	217/674-1 FUGG
Funding Body	DFG-INST
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1016/j.immuni.2017.09.012
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