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

Glodde N, Bald T, Van Den Boorn-Konijnenberg D, Nakamura K, O'Donnell JS, Szczepanski S, Brandes M, Eickhoff S, Das I, Shridhar N, Hinze D, Rogava M, Van Der Sluis TC, Ruotsalainen JJ, Gaffal E, Landsberg J, Ludwig KU, Wilhelm C, Riek-Burchardt M, Mueller AJ, Gebhardt C, Scolyer RA, Long GV, Janzen V, Teng MWL, Kastenmueller W, Mazzone M, Smyth MJ, Tueting T, Hoelzel M (2017)

Publication Type: Journal article

Publication year: 2017

Journal

Immunity Elsevier

Book Volume: 47

Pages Range: 789-802.e9

Journal Issue: 4

DOI: 10.1016/j.immuni.2017.09.012

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. Inhibitors of the receptor tyrosine kinase c-MET are currently used in the clinic to target oncogenic signaling in tumor cells. Glodde et al. now show that c-MET inhibition impairs reactive neutrophil recruitment to tumors and lymph nodes, potentiating T cell anti-tumor immunity. Thus, c-MET inhibitor co-treatment may improve responses to cancer immunotherapy in settings beyond c-MET-dependent tumors.

Involved external institutions

Otto-von-Guericke-Universität Magdeburg DE Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn DE Germany (DE) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) AU Australia (AU) Ruprecht-Karls-Universität Heidelberg DE Germany (DE) Royal Prince Alfred Hospital AU Australia (AU) University of Sydney (USYD) AU Australia (AU) University of Queensland AU Australia (AU) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven BE Belgium (BE)

How to cite

APA:

Glodde, N., Bald, T., Van Den Boorn-Konijnenberg, D., Nakamura, K., O'Donnell, J.S., Szczepanski, S.,... Hoelzel, M. (2017). Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy. Immunity, 47(4), 789-802.e9. https://doi.org/10.1016/j.immuni.2017.09.012

MLA:

Glodde, Nicole, et al. "Reactive Neutrophil Responses Dependent on the Receptor Tyrosine Kinase c-MET Limit Cancer Immunotherapy." Immunity 47.4 (2017): 789-802.e9.

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