Abstract
Simple SummaryRestoring 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.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.
Highlights
One of the potential obstacles to reducing the efficacy of immunotherapy resides in the presence of immunosuppressive cells such as regulatory T cells (Treg)
We have previously shown that a pro-angiogenic factor, the vascular endothelial growth factor-A (VEGF-A) which is highly produced in tumor-bearing hosts, could be involved in the accumulation of Treg and that anti-angiogenic (AA) molecules targeting the VEGF-A/VEGFR pathway could decrease Treg in a mouse model of colorectal cancer and metastatic colorectal cancer patients [2]
Plasmatic Hepatocyte Growth Factor (HGF) level was increased in gastric cancer (GC) patients compared to healthy controls (HC) patients (1407 ± 126 pg/mL vs. 658.6 ± 153 pg/mL, p = 0.031; Supplementary Figure S1A) and was associated with a more advanced disease phenotype since metastatic patients exhibited higher levels of plasmatic HGF than patients with localized disease (1726 ± 136.3 pg/mL vs. 1010 ± 152.9 pg/mL, p = 0.0047; Supplementary Figure S1B), as previously reported [17]
Summary
One of the potential obstacles to reducing the efficacy of immunotherapy resides in the presence of immunosuppressive cells such as regulatory T cells (Treg). We have previously shown that a pro-angiogenic factor, the vascular endothelial growth factor-A (VEGF-A) which is highly produced in tumor-bearing hosts, could be involved in the accumulation of Treg and that anti-angiogenic (AA) molecules targeting the VEGF-A/VEGFR pathway could decrease Treg in a mouse model of colorectal cancer and metastatic colorectal cancer patients [2]. High plasmatic HGF level correlates with poor overall survival in GC patients [9] Beyond these cellular properties, the HGF/c-Met pathway has been involved in immune responses [10,11], notably by different works performed in experimental animal models of inflammatory or autoimmune diseases. We aimed to explore the role of the HGF/c-Met axis and the impact of an anti-HGF antibody (rilotumumab) on circulating Treg in GC patients
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