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

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.

Experimental and stochastic models of melanoma T-cell therapy define impact of subclone fitness on selection of antigen loss variants

“…Images were acquired with an upright LSM780 confocal laser-scanning microscope (Carl Zeiss Microimaging) equipped with a Plan Apochromat 20x/0.8. Image analysis was performed using the Imaris software (Bitplane) as described previously (Bald et al, 2014;Glodde et al, 2017).…”

The interplay between neutrophils and microbiota in cancer

“…Indeed, L‐arginine is a key compound for anti‐tumor activity as it is a substrate in the synthesis of cytotoxic nitric oxide, and is an essential factor for T‐cell metabolism and anti‐tumor activity: IFN‐γ production, T‐cell receptor expression, expansion, and reduced antigen tolerance . Hepatocyte growth factor (HGF) signaling in neutrophils mobilizes them in response to cancer immunotherapies where they acquire immunosuppressive properties (high Il10 , Tgfb2 , Arg1 expression) . Neutrophils also mediate immunosuppression by expressing PD‐L1, recruiting immunosuppressive T regs via CCL17 release (particularly late stage TANs) and inhibiting NK cell‐mediated lytic activity through cleavage of NKp46 .…”

“…[126][127][128][129] Hepatocyte growth factor (HGF) signaling in neutrophils mobilizes them in response to cancer immunotherapies where they acquire immunosuppressive properties (high Il10, Tgfb2, Arg1 expression). 130 Neutrophils also mediate immunosuppression by expressing PD-L1, 130,131 recruiting immunosuppressive T regs via CCL17 release (particularly late stage TANs) 132 and inhibiting NK cell-mediated lytic activity through cleavage of NKp46. 133 Neutrophils can also promote tumors by releasing a multitude of mitogenic cytokines (APRIL, IL-21, IL-17), and factors favoring angiogenesis (MMP9, elastase, VEGF), and tumor progression (HGF, TGF-) ( Fig.…”

Getting TANned: How the tumor microenvironment drives neutrophil recruitment

“…At the inflammation site, neutrophils display a variety of functional responses ranging from phagocytosis and respiratory burst to the extracellular release of their granule contents, which includes proteases and other microbicidal molecules as well as granule protein embedded DNA traps (NETosis) . However, growing evidence suggests a crucial regulatory role for neutrophils in tumor establishment and progression . Recent studies also document the morphological and functional heterogeneity among TANs and their association with protumor or antitumor responses depending on the TME they are part of .…”