Understanding the mechanisms involved in tumor-induced immunosuppression is currently of major interest. Among these immunosuppressive pathways, induction of regulatory T cells (Treg) can inhibit the development of an efficient anti-tumor immune response. Deregulated hepatocyte growth factor (HGF)/c-Met signalling is heavily involved in aggressive cellular invasiveness of human gastric carcinoma. The HGF/c-Met pathway can promote the development of Treg via dendritic cells (DC), but this role has never been reported in human malignancies. We studied the immunomodulatory effects of HGF in gastric carcinoma patients.
The expression of the HGF receptor c-Met was analysed on peripheral blood mononuclear cells using flow cytometry in gastric cancer patients. After that peripheral blood monocytes from these patients were isolated and cultured with GM-CSF and IL-4 (standard condition to induce DC) with or without HGF for 6 days. Then, cells were matured by LPS for 24h. IL-10 production and phenotype were assessed.
No expression of c-Met could be detected in conventional T lymphocytes and Treg (0.36+/-0.13 and 0.55+/-0.20 %respectively) confirming that HGF could not directly act on T cells. But monocytes expressed c-Met (15.95+/-2.97%). This expression was higher in patients with a tumor burden (localized or metastatic), than patients with no tumor burden (20.30 +/- 3.61 vs 3.06 +/- 1.39; p = 0.011). There was no difference of c-Met expression according to the histology and the tumor location. Treatment of monocytes with HGF in the presence of GM-CSF and IL-4 induced the development of cells expressing the DC markers CD11c and HLA-DR, decreased the expression of CD80, CD83 and CD86 co-stimulatory molecules and inhibited their maturation induced by LPS. Furthermore, HGF stimulation increased the secretion of the protolerogenic cytokine IL-10.
Monocytes differentiated in the presence of HGF adopt a protolerogenic phenotype and might induce the development of Treg. Thus, HGF could be a novel immune escape mechanism in cancer and could be targeted not only for its direct anti-tumor effect but also for its immunomodulatory properties.
Clinical trial identification
Legal entity responsible for the study
Cancéropôle Ile-De-France & INCa (2017-1-EMERG-74-INSERM 5-1).
All authors have declared no conflicts of interest.