Targeting HGF/c-Met Axis Decreases Circulating Regulatory T Cells Accumulation in Gastric Cancer Patients.
Juliette PalleLaure HirschAlexandra Lapeyre-ProstDavid MalkaMorgane BourhisSimon PernotElie MarcheteauThibault VoronFlorence CastanAriane LacotteNadine BenhamoudaCorinne TanchotEric FrançoisFrançois GhiringhelliChristelle De La FouchardièreAziz ZaananEric TartourGilles ManceauMagali TermePublished in: Cancers (2021)
Elucidating mechanisms involved in tumor-induced immunosuppression is of great interest since it could help to improve cancer immunotherapy efficacy. Here we show that Hepatocyte Growth Factor (HGF), a pro-tumoral and proangiogenic factor, and its receptor c-Met are involved in regulatory T cells (Treg) accumulation in the peripheral blood of gastric cancer (GC) patients. We observed that c-Met is expressed on circulating monocytes from GC patients. The elevated expression on monocytes is associated with clinical parameters linked to an aggressive disease phenotype and correlates with a worse prognosis. Monocyte-derived dendritic cells from GC patients differentiated in the presence of HGF adopt a regulatory phenotype with a lower expression of co-stimulatory molecules, impaired maturation capacities, and an increased ability to produce interleukin-10 and to induce Treg differentiation in vitro. In the MEGA-ACCORD20-PRODIGE17 trial, GC patients received an anti-HGF antibody treatment (rilotumumab), which had been described to have an anti-angiogenic activity by decreasing proliferation of endothelial cells and tube formation. Rilotumumab decreased circulating Treg in GC patients. Thus, we identified that HGF indirectly triggers Treg accumulation via c-Met-expressing monocytes in the peripheral blood of GC patients. Our study provides arguments for potential alternative use of HGF/c-Met targeted therapies based on their immunomodulatory properties which could lead to the development of new therapeutic associations in cancer patients, for example with immune checkpoint inhibitors.
Keyphrases
- end stage renal disease
- ejection fraction
- peripheral blood
- newly diagnosed
- chronic kidney disease
- regulatory t cells
- peritoneal dialysis
- growth factor
- clinical trial
- poor prognosis
- drug delivery
- randomized controlled trial
- signaling pathway
- mass spectrometry
- cancer therapy
- long non coding rna
- high resolution
- transcription factor
- phase ii
- climate change
- open label
- combination therapy