HGF/c-Met pathway inhibition combined with chemotherapy increases cytotoxic T-cell infiltration and inhibits pancreatic tumour growth and metastasis

Abstract

Pancreatic cancer (PC) is a deadly cancer with a high mortality rate. The unique characteristics of PC, including desmoplasia and immunosuppression, have made it difficult to develop effective treatment strategies. Pancreatic stellate cells (PSCs) play a crucial role in the progression of the disease by interacting with cancer cells. One of the key mediators of PSC - cancer cell interactions is the hepatocyte growth factor (HGF)/c-MET pathway. Using an immunocompetent in vivo model of PC as well as in vitro experiments, this study has shown that a combined approach using HGF/c-MET inhibitors to target stromal-tumour interactions and chemotherapy (gemcitabine) to target cancer cells effectively decreases tumour volume, EMT, and stemness, and importantly, eliminates metastasis. Notably, HGF/c-MET inhibition decreases TGF-beta secretion by cancer cells, resulting in an increase in cytotoxic T-cell infiltration, thus contributing to cancer cell death in tumours. HGF/c-MET inhibition + chemotherapy was also found to normalise the gut microbiome and improve gut microbial diversity. These findings provide a strong platform for assessment of this triple therapy (HGF/c-MET inhibition + chemotherapy) approach in the clinical setting.