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

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.

Circulating low density neutrophils are associated with resistance to anti‐PD1 immunotherapy in squamous head and neck cancer

“…On the other hand, several serum growth factors and cytokines secreted by the tumor or immune cells have been found to act as predictive biomarkers to ICI in other neoplasia, such as interleukin-6 (IL-6), [22][23][24][25] monocyte chemotactic protein 2 (MCP-2) 25 and hepatocyte growth factor (HGF). 25,26 In our ICI cohort, interleukin-7 (IL-7) was a predictive biomarker, since patients having high levels of IL-7 had longer OS, which was not recapitulated in the chemotherapy cohort. Interleukin-7 (IL-7) is a growth factor with a central role in normal T cell development, survival and differentiation [27][28][29] but its role in neutrophil biology has attracted less attention.…”

Lrig1-expression confers suppressive function to CD4+ cells and is essential for averting autoimmunity via the Smad2/3/Foxp3 axis

“…Alternatively, intracellular signaling context and transcription factor functional network constellation might be quite different between cancer cells and T reg cells. It may be possible that other or unidentified members of the receptor tyrosine kinase (RTK) family, such as c-MET, AXL, MERTK, or VEGFR, or an unknown surface protein associated with tyrosine kinase, can be involved in the Lrig1-mediated intracellular signaling pathway in T reg cells 65 – 67 . In the EAE animal model, 6F01 mAb showed the equivalent level of therapeutic potential to anti-IL-17A mAb in a dose-dependent manner.…”

Decrease of Pro-Angiogenic Monocytes Predicts Clinical Response to Anti-Angiogenic Treatment in Patients with Metastatic Renal Cell Carcinoma

“…This decrease improved the immunosuppression condition of T cells, but did not appear to influence patient survival [ 45 , 49 ]. The relationship between this population of pro-angiogenic monocytes described in this work and the recently described population of immunosuppressive monocytes expressing cMet is not yet known [ 50 ].…”