HGF/MET and the Immune System: Relevance for Cancer Immunotherapy

Abstract

An overactivation of hepatocyte growth factor (HGF)/mesenchymal-epithelial transition factor (MET) axis promotes tumorigenesis and tumor progression in various cancer types. Research data recently evidenced that HGF/MET signaling is also involved also in the immune response, mainly modulating dendritic cells functions. In general, the pathway seems to play an immunosuppressive role, thus hypothesizing that it could constitute a mechanism of primary and acquired resistance to cancer immunotherapy. Recently, some approaches are being developed, including drug design and cell therapy to combine MET and programmed cell death receptor-1 (PD-1)/programmed cell death receptor-ligand 1 (PD-L1) inhibition. This approach could represent a new weapon in cancer therapy in the future.

Noncoding microdeletion in mouseHgfdisrupts neural crest migration into the stria vascularis, reduces the endocochlear potential and suggests the neuropathology for human nonsyndromic deafness DFNB39

“…Hepatocyte growth factor (HGF) is an activator of mitosis and identical to “scatter factor”, which stimulates epithelial cells to disperse in culture (Stoker et al, 1987; Nakamura, 1989). HGF is also implicated in branching morphogenesis (Zhang and Vande Woude, 2003), tumorigenesis (Zhang et al, 2018), immune cell regulation (Papaccio et al, 2018), neuronal survival (Thompson et al, 2004; Nakano et al, 2017), wound healing (Miyagi et al, 2018), neuronal differentiation, synapse formation and maturation (Matsumoto et al, 2014). There are numerous studies of HGF structure, domains, splice isoforms and diverse functions (Comoglio et al, 2003; Matsumoto et al, 2014).…”

Flagellin adjuvanted F1/V subunit plague vaccine induces T cell and functional antibody responses with unique gene signatures

“…50 MET modulates dendritic cells to play an immunosuppressive role. 51 The reasons why LTBR which is important for homeostasis of dendritic cells, 52 IL1R1 which is important for IL-17 generation, and IL-1 function 53 and CCL19 which enhances Th1 immunity 54 are down regulated are not clear.…”

Biomarkers of Response to Combinational Use of PD-1 Blockade and Anti-angiogenesis: An Analysis from a Phase II Trial in Advanced Triple-negative Breast Cancer Patients

“…Using the ProcartaPlexHuman Cytokine/Chemokine/Growth Factor Panel and the ProcartaPlexHuman Immuno-Oncology Checkpoint Panel, we found that patients with lower baseline plasma HGF or IL-8 levels, or a decrease of plasma IL-8, or an increase of plasma TIM-3 or CD152 level at 8 weeks after treatment may bene t more from camrelizumab with apatinib. Recent studies showed that high serum levels of the c-MET ligand HGF correlated with increasing neutrophil counts, which was associated with poor responses to checkpoint blockade therapies (17)(18)(19)(20). IL-8 is secreted by malignant tumor and stroma cells across many different types of tumor, and is a member of the CXC chemokine family identi ed as a chemotactic factor for neutrophils (21)(22)(23).…”