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Simple Summary  Restoring an effective immune response is the key goal of immunotherapy. One of the major mechanisms of tumor-induced immunosuppression is regulatory T cells (Treg) accumulation. In this study, using in vitro and in vivo analysis, we assessed the impact of the HGF/c-Met pathway, involved notably in tumor angiogenesis, on Treg accumulation in patients with gastric cancer. First, we reported that c-Met is expressed on circulating monocytes of gastric cancer patients and this expression seems to be associated with the worst outcome. Secondly, during in vitro cultures, c-Met+ monocytes differentiate into dendritic cells with tolerogenic properties able to induce the proliferation of Treg. Finally, rilotumumab, an anti-HGF antibody, decreases the percentage of circulating Treg in gastric cancer patients. Using HGF/c-Met inhibitors to partially reverse immunosuppression could lead to the development of new treatment associations, for example with immune checkpoint blockers.    Abstract  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.

Targeting HGF/c-Met Axis Decreases Circulating Regulatory T Cells Accumulation in Gastric Cancer Patients