HGF/c-Met pathway inhibition combined with chemotherapy increases cytotoxic T-cell infiltration and inhibits pancreatic tumour growth and metastasis
Alpha Raj Mekapogu, Zhihong Xu, Srinivasa Pothula, Chamini J. Perera, Tony Pang, S. M. Zahid Hosen, Vishnu C. Damalanka, James W. Janetka, David Goldstein, Romano C. Pirola, Jeremy S. Wilson, Minoti V. Apte
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-β 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.