4 years ago

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

Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy
Indrajit Das, Massimiliano Mazzone, Daniel Hinze, Naveen Shridhar, Sabrina Szczepanski, Kyohei Nakamura, Georgina V. Long, Andreas J. Müller, Monika Riek-Burchardt, Michael Hölzel, Janne J. Ruotsalainen, Wolfgang Kastenmüller, Viktor Janzen, Maria Brandes, Christoffer Gebhardt, Nicole Glodde, Michele W.L. Teng, Evelyn Gaffal, Thomas Tüting, Christoph Wilhelm, Kerstin U. Ludwig, Jake S. O’Donnell, Mark J. Smyth, Jennifer Landsberg, Tobias Bald, Richard A. Scolyer, Meri Rogava, Sarah Eickhoff, Tetje C. van der Sluis, Debby van den Boorn-Konijnenberg


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.

Publisher URL: http://www.cell.com/immunity/fulltext/S1074-7613(17)30423-5

DOI: 10.1016/j.immuni.2017.09.012

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